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Alzheimer's treatments: what's on the horizon.

Despite many promising leads, new treatments for Alzheimer's are slow to emerge.

Current Alzheimer's treatments temporarily improve symptoms of memory loss and problems with thinking and reasoning.

These Alzheimer's treatments boost the performance of chemicals in the brain that carry information from one brain cell to another. They include cholinesterase inhibitors and the medicine memantine (Namenda). However, these treatments don't stop the underlying decline and death of brain cells. As more cells die, Alzheimer's disease continues to progress.

Experts are cautious but hopeful about developing treatments that can stop or delay the progression of Alzheimer's. Experts continue to better understand how the disease changes the brain. This has led to the research of potential Alzheimer's treatments that may affect the disease process.

Future Alzheimer's treatments may include a combination of medicines. This is similar to treatments for many cancers or HIV / AIDS that include more than one medicine.

These are some of the strategies currently being studied.

Taking aim at plaques

Some of the new Alzheimer's treatments target clumps of the protein beta-amyloid, known as plaques, in the brain. Plaques are a characteristic sign of Alzheimer's disease.

Strategies aimed at beta-amyloid include:

Recruiting the immune system. Medicines known as monoclonal antibodies may prevent beta-amyloid from clumping into plaques. They also may remove beta-amyloid plaques that have formed. They do this by helping the body clear them from the brain. These medicines mimic the antibodies your body naturally produces as part of your immune system's response to foreign invaders or vaccines.

In 2023, the U.S. Food and Drug Administration (FDA) approved lecanemab (Leqembi) for people with mild Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease.

A phase 3 clinical trial found that the medicine slowed cognitive decline in people with early Alzheimer's disease. The medicine prevents amyloid plaques in the brain from clumping. The phase 3 trial was the largest so far to study whether clearing clumps of amyloid plaques from the brain can slow the disease.

Lecanemab is given as an IV infusion every two weeks. Your care team likely will watch for side effects and ask you or your caregiver how your body reacts to the drug. Side effects of lecanemab include infusion-related reactions such as fever, flu-like symptoms, nausea, vomiting, dizziness, changes in heart rate and shortness of breath.

Also, people taking lecanemab may have swelling in the brain or may get small bleeds in the brain. Rarely, brain swelling can be serious enough to cause seizures and other symptoms. Also in rare instances, bleeding in the brain can cause death. The FDA recommends getting a brain MRI before starting treatment. It also recommends being monitored with brain MRI s during treatment for symptoms of brain swelling or bleeding.

People who carry a certain form of a gene known as APOE e4 appear to have a higher risk of these serious complications. The FDA recommends being tested for this gene before starting treatment with lecanemab.

If you take a blood thinner or have other risk factors for brain bleeding, talk to your health care professional before taking lecanemab. Blood-thinning medicines may increase the risk of bleeds in the brain.

More research is being done on the potential risks of taking lecanemab. Other research is looking at how effective lecanemab may be for people at risk of Alzheimer's disease, including people who have a first-degree relative, such as a parent or sibling, with the disease.

Another medicine being studied is donanemab. It targets and reduces amyloid plaques and tau proteins. It was found to slow declines in thinking and functioning in people with early Alzheimer's disease.

The monoclonal antibody solanezumab did not show benefits for individuals with preclinical, mild or moderate Alzheimer's disease. Solanezumab did not lower beta-amyloid in the brain, which may be why it wasn't effective.

Preventing destruction. A medicine initially developed as a possible cancer treatment — saracatinib — is now being tested in Alzheimer's disease.

In mice, saracatinib turned off a protein that allowed synapses to start working again. Synapses are the tiny spaces between brain cells through which the cells communicate. The animals in the study experienced a reversal of some memory loss. Human trials for saracatinib as a possible Alzheimer's treatment are now underway.

Production blockers. These therapies may reduce the amount of beta-amyloid formed in the brain. Research has shown that beta-amyloid is produced from a "parent protein" in two steps performed by different enzymes.

Several experimental medicines aim to block the activity of these enzymes. They're known as beta- and gamma-secretase inhibitors. Recent studies showed that the beta-secretase inhibitors did not slow cognitive decline. They also were associated with significant side effects in those with mild or moderate Alzheimer's. This has decreased enthusiasm for the medicines.

Keeping tau from tangling

A vital brain cell transport system collapses when a protein called tau twists into tiny fibers. These fibers are called tangles. They are another common change in the brains of people with Alzheimer's. Researchers are looking at a way to prevent tau from forming tangles.

Tau aggregation inhibitors and tau vaccines are currently being studied in clinical trials.

Reducing inflammation

Alzheimer's causes chronic, low-level brain cell inflammation. Researchers are studying ways to treat the processes that lead to inflammation in Alzheimer's disease. The medicine sargramostim (Leukine) is currently in research. The medicine may stimulate the immune system to protect the brain from harmful proteins.

Researching insulin resistance

Studies are looking into how insulin may affect the brain and brain cell function. Researchers are studying how insulin changes in the brain may be related to Alzheimer's. However, a trial testing of an insulin nasal spray determined that the medicine wasn't effective in slowing the progression of Alzheimer's.

Studying the heart-head connection

Growing evidence suggests that brain health is closely linked to heart and blood vessel health. The risk of developing dementia appears to increase as a result of many conditions that damage the heart or arteries. These include high blood pressure, heart disease, stroke, diabetes and high cholesterol.

A number of studies are exploring how best to build on this connection. Strategies being researched include:

• Current medicines for heart disease risk factors. Researchers are looking into whether blood pressure medicines may benefit people with Alzheimer's. They're also studying whether the medicines may reduce the risk of dementia.
• Medicines aimed at new targets. Other studies are looking more closely at how the connection between heart disease and Alzheimer's works at the molecular level. The goal is to find new potential medicines for Alzheimer's.
• Lifestyle choices. Research suggests that lifestyle choices with known heart benefits may help prevent Alzheimer's disease or delay its onset. Those lifestyle choices include exercising on most days and eating a heart-healthy diet.

Studies during the 1990s suggested that taking hormone replacement therapy during perimenopause and menopause lowered the risk of Alzheimer's disease. But further research has been mixed. Some studies found no cognitive benefit of taking hormone replacement therapy. More research and a better understanding of the relationship between estrogen and cognitive function are needed.

Speeding treatment development

Developing new medicines is a slow process. The pace can be frustrating for people with Alzheimer's and their families who are waiting for new treatment options.

To help speed discovery, the Critical Path for Alzheimer's Disease (CPAD) consortium created a first-of-its-kind partnership to share data from Alzheimer's clinical trials. CPAD 's partners include pharmaceutical companies, nonprofit foundations and government advisers. CPAD was formerly called the Coalition Against Major Diseases.

CPAD also has collaborated with the Clinical Data Interchange Standards Consortium to create data standards. Researchers think that data standards and sharing data from thousands of study participants will speed development of more-effective therapies.

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• Treatments and research. Alzheimer's Association. https://www.alz.org/alzheimers-dementia/research_progress/treatment-horizon. Accessed March 23, 2023.
• Cummings J, et al. Alzheimer's disease drug development pipeline: 2022. Alzheimer's and Dementia. 2022; doi:10.1002/trc2.12295.
• Burns S, et al. Therapeutics of Alzheimer's disease: Recent developments. Antioxidants. 2022; doi:10.3390/antiox11122402.
• Plascencia-Villa G, et al. Lessons from antiamyloid-beta immunotherapies in Alzheimer's disease. Handbook of Clinical Neurology. 2023; doi:10.1016/B978-0-323-85555-6.00019-9.
• Brockmann R, et al. Impacts of FDA approval and Medicare restriction on antiamyloid therapies for Alzheimer's disease: Patient outcomes, healthcare costs and drug development. The Lancet Regional Health. 2023; doi:10.1016/j.lana. 2023.100467 .
• Wojtunik-Kulesza K, et al. Aducanumab — Hope or disappointment for Alzheimer's disease. International Journal of Molecular Sciences. 2023; doi:10.3390/ijms24054367.
• Can Alzheimer's disease be prevented? Alzheimer's Association. http://www.alz.org/research/science/alzheimers_prevention_and_risk.asp. Accessed March 23, 2023.
• Piscopo P, et al. A systematic review on drugs for synaptic plasticity in the treatment of dementia. Ageing Research Reviews. 2022; doi:10.1016/j.arr. 2022.101726 .
• Facile R, et al. Use of Clinical Data Interchange Standards Consortium (CDISC) standards for real-world data: Expert perspectives from a qualitative Delphi survey. JMIR Medical Informatics. 2022; doi:10.2196/30363.
• Imbimbo BP, et al. Role of monomeric amyloid-beta in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies. Pharmacological Research. 2023; doi:10.1016/j.phrs. 2022.106631 .
• Conti Filho CE, et al. Advances in Alzheimer's disease's pharmacological treatment. Frontiers in Pharmacology. 2023; doi:10.3389/fphar. 2023.1101452 .
• Potter H, et al. Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease. Alzheimer's and Dementia. 2021; doi:10.1002/trc2.12158.
• Zhong H, et al. Effect of peroxisome proliferator-activated receptor-gamma agonists on cognitive function: A systematic review and meta-analysis. Biomedicines. 2023; doi:10.3390/biomedicines11020246.
• Grodstein F. Estrogen and cognitive function. https://www.uptodate.com/contents/search. Accessed March 23, 2023.
• Mills ZB, et al. Is hormone replacement therapy a risk factor or a therapeutic option for Alzheimer's disease? International Journal of Molecular Sciences. 2023; doi:10.3390/ijms24043205.
• Custodia A, et al. Biomarkers assessing endothelial dysfunction in Alzheimer's disease. Cells. 2023; doi:10.3390/cells12060962.
• Overview. Critical Path for Alzheimer's Disease. https://c-path.org/programs/cpad/. Accessed March 29, 2023.
• Shi M, et al. Impact of anti-amyloid-β monoclonal antibodies on the pathology and clinical profile of Alzheimer's disease: A focus on aducanumab and lecanemab. Frontiers in Aging and Neuroscience. 2022; doi:10.3389/fnagi. 2022.870517 .
• Leqembi (approval letter). Biologic License Application 761269. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761269. Accessed July 7, 2023.
• Van Dyck CH, et al. Lecanemab in early Alzheimer's disease. New England Journal of Medicine. 2023; doi:10.1056/NEJMoa2212948.
• Leqembi (prescribing information). Eisai; 2023. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=761269. Accessed July 10, 2023.

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Lecanemab, the New Alzheimer’s Treatment: 3 Things To Know

BY CARRIE MACMILLAN July 24, 2023

Yale researcher discusses the recent FDA approval of a new Alzheimer's disease treatment.

[Originally published January 19, 2023. Updated: July 24, 2023.]

The Food and Drug Administration (FDA) recently granted full approval to a new Alzheimer’s treatment called lecanemab, which has been shown to moderately slow cognitive and functional decline in early-stage cases of the disease.

Alzheimer’s disease is a progressive disorder that damages and destroys nerve cells in the brain. Over time, the disease leads to a gradual loss of cognitive functions, including the ability to remember, reason, use language, and recognize familiar places. It can also cause a range of behavioral changes.

In January, the FDA gave the medication an accelerated approval based on amyloid plaque clearance. Christopher van Dyck, MD , director of Yale’s Alzheimer’s Disease Research Unit, was the lead author of a study published in the Jan. 5 issue of The New England Journal of Medicine that shared results of a Phase III clinical trial of lecanemab. (Dr. van Dyck is also a paid consultant for the pharmaceutical company Eisai, which funded the trials.)

Sold under the brand name Leqembi™ and made by Eisai in partnership with Biogen Inc., the drug is delivered by an intravenous infusion every two weeks. Lecanemab works by removing a sticky protein from the brain that is believed to cause Alzheimer’s disease to advance.

“It’s very exciting because this is the first treatment in our history that shows an unequivocal slowing of decline in Alzheimer’s disease,” says Dr. van Dyck.

This is the first time in two decades that the FDA has granted full approval to a drug for Alzheimer’s, but there is also a “black box” warning on the medication—the agency’s strongest caution—because of safety concerns.

We talked more with Dr. van Dyck, who answered three questions about the new treatment.

How effective is lecanemab for Alzheimer’s disease?

In a trial that involved 1,795 participants with early-stage, symptomatic Alzheimer’s, lecanemab slowed clinical decline by 27% after 18 months of treatment compared with those who received a placebo.

“The antibody treatment selectively targets the forms of amyloid protein that are thought to be the most toxic to brain cells,” says Dr. van Dyck.

Study participants who received the treatment had a significant reduction in amyloid burden in imaging tests, usually reaching normal levels by the end of the trial. Participants also showed a 26% slowing of decline in a key secondary measure of cognitive function and a 37% slowing of decline in a measure of daily living compared to the placebo group.

“Would I like the numbers to be higher? Of course, but I don’t think this is a small effect,” says Dr. van Dyck. “These results could also indicate a starting point for bigger effects. The data appear encouraging that the longer the treatment period, the better the effect. But we’ll need more studies to determine if that’s true.”

They also beg the question about still-earlier intervention, adds Dr. van Dyck. Lecanemab is already being tested in the global AHEAD study for individuals who are still cognitively normal but at high risk of symptoms due to elevated levels of brain amyloid.

Yale currently has the largest number of participants in the AHEAD study, which is funded by the National Institutes of Health (NIH) and Eisai and is enrolling participants as young as 55. “We may see a larger benefit if we intervene before significant brain damage has occurred,” he says.

Is lecanemab safe?

The most common side effect (26.4% of participants vs. 7.4% in the placebo group) of the treatment is an infusion-related reaction, which may include transient symptoms, such as flushing, chills, fever, rash, and body aches. The majority (96%) of these reactions were mild to moderate, and 75% happened after the first dose.

“We can medicate those individuals in advance if we find they have those side effects repeatedly,” says Dr. van Dyck. “We can use medications such as diphenhydramine or acetaminophen. But this is generally not an issue.”

Another potential side effect associated with lecanemab was amyloid-related imaging abnormalities with edema, or fluid formation on the brain. This occurred in 12.6% of trial participants compared to 1.7% in the placebo group. “It’s usually asymptomatic when it occurs, but we can detect it on MRI scans. We often don’t stop dosing if we see it, unless there are symptoms, in which case we would pause infusions until it fully resolves,” Dr. van Dyck says.

It’s important to note that the studies with lecanemab show substantially lower rates of this side effect than do published trials of other, similar drugs such as aducanumab—they're at about a third of the rate, explains Dr. van Dyck. “So, for drugs in this class, I think lecanemab has a favorable safety profile,” he says.

Lastly, 17.3% of trial participants experienced amyloid-related imaging abnormalities with brain bleeding compared to 9% in the placebo group.

“Most of the time we're really talking about microhemorrhages that are in the order of millimeters,” says Dr. van Dyck. “People with Alzheimer's disease are more prone to these events because of the amyloid deposits in their blood vessels, but a catastrophic bleed is quite rare.”

The medication’s label includes warnings about brain swelling and bleeding and that people with a gene mutation that increases their risk of Alzheimer’s disease are at greater risk of brain swelling on the treatment. The label also cautions against taking blood thinners while on the medication.

When will lecanemab be available for Alzheimer’s disease treatment?

Eisai set the price for Leqembi at $26,500 per year, and it has reportedly been largely unavailable while FDA full approval was pending. That may change now that Medicare has said it will cover 80% of the cost.

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Expert discusses recent lecanemab trial, why it appears to offer hope for those with deadly disease

Researchers say we appear to be at the start of a new era for Alzheimer’s treatment. Trial results published in January showed that for the first time a drug has been able to slow the cognitive decline characteristic of the disease. The drug, lecanemab, is a monoclonal antibody that works by binding to a key protein linked to the malady, called amyloid-beta, and removing it from the body. Experts say the results offer hope that the slow, inexorable loss of memory and eventual death brought by Alzheimer’s may one day be a thing of the past.

The Gazette spoke with Scott McGinnis , an assistant professor of neurology at Harvard Medical School and Alzheimer’s disease expert at Brigham and Women’s Hospital , about the results and a new clinical trial testing whether the same drug given even earlier can prevent its progression.

Scott McGinnis

GAZETTE: The results of the Clarity AD trial have some saying we’ve entered a new era in Alzheimer’s treatment. Do you agree?

McGINNIS: It’s appropriate to consider it a new era in Alzheimer’s treatment. Until we obtained the results of this study, trials suggested that the only mode of treatment was what we would call a “symptomatic therapeutic.” That might give a modest boost to cognitive performance — to memory and thinking and performance in usual daily activities. But a symptomatic drug does not act on the fundamental pathophysiology, the mechanisms, of the disease. The Clarity AD study was the first that unambiguously suggested a disease-modifying effect with clear clinical benefit. A couple of weeks ago, we also learned a study with a second drug, donanemab, yielded similar results.

GAZETTE: Hasn’t amyloid beta, which forms Alzheimer’s characteristic plaques in the brain and which was the target in this study, been a target in previous trials that have not been effective?

McGINNIS: That’s true. Amyloid beta removal has been the most widely studied mechanism in the field. Over the last 15 to 20 years, we’ve been trying to lower beta amyloid, and we’ve been uncertain about the benefits until this point. Unfavorable results in study after study contributed to a debate in the field about how important beta amyloid is in the disease process. To be fair, this debate is not completely settled, and the results of Clarity AD do not suggest that lecanemab is a cure for the disease. The results do, however, provide enough evidence to support the hypothesis that there is a disease-modifying effect via amyloid removal.

GAZETTE: Do we know how much of the decline in Alzheimer’s is due to beta amyloid?

McGINNIS: There are two proteins that define Alzheimer’s disease. The gold standard for diagnosing Alzheimer’s disease is identifying amyloid beta plaques and tau neurofibrillary tangles. We know that amyloid beta plaques form in the brain early, prior to accumulation of tau and prior to changes in memory and thinking. In fact, the levels and locations of tau accumulation correlate much better with symptoms than the levels and locations of amyloid. But amyloid might directly “fuel the fire” to accelerated changes in tau and other downstream mechanisms, a hypothesis supported by basic science research and the findings in Clarity AD that treatment with lecanemab lowered levels of not just amyloid beta but also levels of tau and neurodegeneration in the blood and cerebrospinal fluid.

GAZETTE: In the Clarity AD trial, what’s the magnitude of the effect they saw?

McGINNIS: The relevant standards in the trial — set by the FDA and others — were to see two clinical benefits for the drug to be considered effective. One was a benefit on tests of memory and thinking, a cognitive benefit. The other was a benefit in terms of the performance in usual daily activities, a functional benefit. Lecanemab met both of these standards by slowing the rate of decline by approximately 25 to 35 percent compared to placebo on measures of cognitive and functional decline over the 18-month studies.

“In a perfect world, we’d have treatments that completely stop decline and even restore function. We’re not there yet, but this represents an important step toward that goal.”

Steven M. Smith

GAZETTE: What are the key questions that remain?

McGINNIS: An important question relates to the stages at which the interventions were done. The study was done in subjects with mild cognitive impairment and mild Alzheimer dementia. People who have mild cognitive impairment have retained their independence in instrumental activities of daily living — for example, driving, taking medications, managing finances, errands, chores — but have cognitive and memory changes beyond what we would attribute to normal aging. When people transition to mild dementia, they’re a bit further along. The study was for people within that spectrum but there’s some reason to believe that intervening even earlier might be more effective, as is the case with many other medical conditions.

We’re doing a study here called the AHEAD study that is investigating the effects of lecanemab when administered earlier, in cognitively normal individuals who have elevated brain amyloid, to see whether we see a preventative benefit. The hope is that we would at least see a delay to onset of cognitive impairment and a favorable effect not only on amyloid biomarkers, but other biomarkers that might capture progression of the disease.

GAZETTE: Is anybody in that study treatment yet or are you still enrolling?

McGINNIS: There’s a rolling enrollment, so there are people who are in the double-blind phase of treatment, receiving either the drug or the placebo. But the enrollment target hasn’t been reached yet so we’re still accepting new participants.

GAZETTE: Is it likely that we may see drug cocktails that go after tau and amyloid? Is that a future approach?

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McGINNIS: It has not yet been tried, but those of us in the field are very excited at the prospect of these studies. There’s been a lot of work in recent years on developing therapeutics that target tau, and I think we’re on the cusp of some important breakthroughs. This is key, considering evidence that spreading of tau from cell to cell might contribute to progression of the disease. Additionally, for some time, we’ve had a suspicion that we will likely have to target multiple different aspects of the disease process, as is the case with most types of cancer treatment. Many in our field believe that we will obtain the most success when we identify the most pertinent mechanisms for subgroups of people with Alzheimer’s disease and then specifically target those mechanisms. Examples might include metabolic dysfunction, inflammation, and problems with elements of cellular processing, including mitochondrial functioning and processing old or damaged proteins. Multi-drug trials represent a natural next step.

GAZETTE: What about side effects from this drug?

McGINNIS: We’ve known for a long time that drugs in this class, antibodies that harness the power of the immune system to remove amyloid, carry a risk of causing swelling in the brain. In most cases, it’s asymptomatic and just detected by MRI scan. In Clarity AD, while 12 to 13 percent of participants receiving lecanemab had some level of swelling detected by MRI, it was symptomatic in only about 3 percent of participants and mild in most of those cases.

Another potential side effect is bleeding in the brain or on the surface of the brain. When we see bleeding, it’s usually very small, pinpoint areas of bleeding in the brain that are also asymptomatic. A subset of people with Alzheimer’s disease who don’t receive any treatment are going to have these because they have amyloid in their blood vessels, and it’s important that we screen for this with an MRI scan before a person receives treatment. In Clarity AD, we saw a rate of 9 percent in the placebo group and about 17 percent in the treatment group, many of those cases in conjunction with swelling and mostly asymptomatic.

The scenario that everybody worries about is a hemorrhagic stroke, a larger area of bleeding. That was much less common in this study, less than 1 percent of people. Unlike similar studies, this study allowed subjects to be on anticoagulation medications, which thin the blood to prevent or treat clots. The rate of macro hemorrhage — larger bleeds — was between 2 and 3 percent in the anticoagulated participants. There were some highly publicized cases including a patient who had a stroke, presented for treatment, received a medication to dissolve clots, then had a pretty bad hemorrhage. If the drug gets full FDA approval, is covered by insurance, and becomes clinically available, most physicians are probably not going to give it to people who are on anticoagulation. These are questions that we’ll have to work out as we learn more about the drug from ongoing research.

GAZETTE: Has this study, and these recent developments in the field, had an effect on patients?

McGINNIS: It has had a considerable impact. There’s a lot of interest in the possibility of receiving this drug or a similar drug, but our patients and their family members understand that this is not a cure. They understand that we’re talking about slowing down a rate of decline. In a perfect world, we’d have treatments that completely stop decline and even restore function. We’re not there yet, but this represents an important step toward that goal. So there’s hope. There’s optimism. Our patients, particularly patients who are at earlier stages of the disease, have their lives to live and are really interested in living life fully. Anything that can help them do that for a longer period of time is welcome.

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Current and Future Treatments in Alzheimer Disease: An Update

Konstantina g yiannopoulou.

1 Memory Center, Neurological Department, Henry Dunant Hospital Center, Athens, Greece

Sokratis G Papageorgiou

2 Cognitive Disorders/Dementia Unit, 2nd Neurological Department, National and Kapodistrian University of Athens, Attikon General University Hospital, Athens, Greece

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

Introduction

Alzheimer disease (AD) is one of the greatest medical care challenges of our century and is the main cause of dementia. In total, 40 million people are estimated to suffer from dementia throughout the world, and this number is supposed to become twice as much every 20 years, until approximately 2050. 1

Because dementia occurs mostly in people older than 60 years, the growing expansion of lifespan, leading to a rapidly increasing number of patients with dementia, 2 mainly AD, has led to an intensive growth in research focused on the treatment of the disease. However, despite all arduous research efforts, at the moment, there are no effective treatment options for the disease. 3 , 4

The basic pathophysiology and neuropathology of AD that drives the current research suggests that the primary histopathologic lesions of AD are the extracellular amyloid plaques and the intracellular Tau neurofibrillary tangles (NFTs). 5 The amyloid or senile plaques (SPs) are constituted chiefly of highly insoluble and proteolysis-resistant peptide fibrils produced by β-amyloid (Aβ) cleavage. Aβ peptides with Aβ38, Aβ40, and Aβ42 as the most common variants are produced after the sequential cleavage of the large precursor protein amyloid precursor protein (APP) by the 2 enzymes, β-secretase (BACE1) and γ-secretase. Nevertheless, Aβ is not formed if APP is first acted on and cleaved by the enzyme α-secretase instead of β-secretase. 6 According to the “amyloid hypothesis” Aβ production in the brain initiates a cascade of events leading to the clinical syndrome of AD. It is the forming of amyloid oligomers to which neurotoxicity is mainly attributed and initiates the amyloid cascade. The elements of the cascade include local inflammation, oxidation, excitoxicity (excessive glutamate), and tau hyperphosphorylation. 5 Tau protein is a microtubule-associated protein which binds microtubules in cells to facilitate the neuronal transport system. Microtubules also stabilize growing axons necessary for neuronal development and function. Abnormally hyperphosphorylated tau forms insoluble fibrils and folds into intraneuronic tangles. Consequently, it uncouples from microtubules, inhibits transport, and results in microtubule disassembly. 6 Although in the amyloid hypothesis, tau hyperphosphorylation was thought to be a downstream event of Aβ deposition, it is equally probable that tau and Aβ act in parallel pathways causing AD and enhancing each other’s toxic effects. 3 Progressive neuronal destruction leads to shortage and imbalance between various neurotransmitters (eg, acetylcholine, dopamine, serotonin) and to the cognitive deficiencies seen in AD. 5

All of the already established treatments that are used today try to counterbalance the neurotransmitter imbalance of the disease. The acetylocholinesterase inhibitors (AChEIs) which are approved for the treatment of AD are donepezil, galantamine, and rivastigmine. 4 , 5 Their development was based in the cholinergic hypothesis which suggests that the progressive loss of limbic and neocortical cholinergic innervation in AD is critically important for memory, learning, attention, and other higher brain functions decline. Furthermore, neurofibrillary degeneration in the basal forebrain is probably the primary cause for the dysfunction and death of cholinergic neurons in this region, giving rise to a widespread presynaptic cholinergic denervation. The AChEIs increase the availability of acetylcholine at synapses and have been proven clinically useful in delaying the cognitive decline in AD. 7

A further therapeutic agent approved for moderate to severe AD is the low-to-moderate affinity, noncompetitive N -methyl- d -aspartate (NMDA) receptor antagonist memantine. 4 , 5 Memantine binds preferentially to open NMDA receptor–operated calcium channels blocking NMDA-mediated ion flux and ameliorating the dangerous effects of pathologically elevated glutamate levels that lead to neuronal dysfunction. 8

In clinical trials, both Aβ and tau are prime targets for disease-modifying treatments (DMTs) in AD. From this point of view, AD could be prevented or effectively treated by decreasing the production of Aβ and tau; preventing aggregation or misfolding of these proteins; neutralizing or removing the toxic aggregate or misfolded forms of these proteins; or a combination of these modalities. 7

A number of additional pathogenic mechanisms have been described, possibly overlapping with Aβ plaques and NFT formation or induced by them, including inflammation, oxidative damage, iron deregulation, and cholesterol metabolism blood-brain barrier (BBB) dysfunction or α-synuclein toxicity. 9 - 13

This article will review current nonpharmacological and pharmacological management of the cognitive and behavioral symptoms of AD, with a focus on the medications that are currently FDA (Food and Drug Administration)–approved for the treatment of the cognitive and functional deficits of AD. 10 Pharmacological agents under research in phase 1, 2, and 3 clinical trials in AD will be summarized. 11 - 13

Current management of AD

A multifactorial tailored management of AD is attempted nowadays based in the following components:

• Open physician, caregiver, and patient communication: a sincere and successful conveying of information and feelings between them will offer opportune identifying of symptoms, exact evaluation and diagnosis, and suitable guidance.
• - Consistency and simplification of environment 10 ;
• - Established routines 10 ;
• - Communicative strategies such as calm interactions, providing pleasurable activities, using simple language and “saying no” only when safety is concerned 10 ;
• - Timely planning for legal and medical decisions and needs 10 ;
• - Cognitive behavioral therapy 14 , 15 ;
• - Exercise therapy, light therapy, music therapy. 14 , 15
• - Planned short rest periods for the caregiver;
• - Psychoeducation including preparing for effects of dementia on cognition, function and behaviors, expectations, avoiding situations that can worsen the symptoms or increasing the dangers for safety and well-being
• - Encouraging the development of support networks for the caregivers. 10
• Pharmacological interventions.

FDA-approved AD medications

The AChEIs donepezil, galantamine, rivastigmine, and the NMDA antagonist memantine are the only FDA-approved AD medications. 10

AChEIs attempt at reducing the breakdown of acetylcholine levels in the brain of the patients with AD by inhibiting the responsible enzyme acetylcholinesterase in the synaptic cleft. 5 Thus, AChEIs enhance central cholinergic neurotransmission and finally tend to mitigate decline in cognition at least during the first year of treatment. Further decline occurs, but even temporary discontinuation of these drugs results in rapid decline and is associated with greater risk of nursing home placement. 16

Initiation of AChEI treatment as soon as possible after the diagnosis is preferred as patients who started the AChEI 6 months later showed more rapid cognitive decline than those who started the drug immediately. 17 All 3 AChEIs have proved their treatment benefits in delaying decline, stabilizing, or even improving cognition and activities of daily living in randomized placebo-controlled trials up to 52 weeks duration. 10 , 18 Longer term open-label extension studies support also longer term treatment benefits. 10

Significant efficacy differences among the AChEIs have not been reported. Donepezil and rivastigmine have been approved by FDA for mild, moderate, and severe AD, whereas galantamine for mild and moderate AD. 18

The most common adverse effects are triggered by the cholinomimetic action of the AChEIs on the gastrointestinal tract and often include diarrhea, nausea, and vomiting. Rapid eye movement sleep behavior disorder has been also remarked in some individuals. Administration of the drug after a meal in the morning can minimize all of these adverse effects. The transdermal patch of rivastigmine can induce rash at the site of application. Adverse effects affect usually a 5% to 20% of patients but are mostly transient and mild. The AChEIs may also trigger bradycardia and increase the risk of syncope. Thus, AChEIs are contraindicated in conditions including severe cardiac arrhythmias, especially bradycardia or syncope. They are also contraindicated in active peptic ulcer or gastrointestinal bleeding history and uncontrolled seizures. Slow titration over months to years to a maximal tolerated of the indicated dose is important for the safety of the patients. 17 , 18

Pharmacokinetic characteristics differ among AChEIs: the primary route of elimination for donepezil and galantamine is hepatic metabolism, whereas for rivastigmine is liver and intestine metabolism. Donepezil and galantamine inhibit selectively and reversibly the acetylcholinesterase, whereas rivastigmine is a “pseudo-irreversible” inhibitor of acetylcholinesterase and butyrylcholinesterase. Donepezil has a long elimination half-life of 70 hours and galantamine of 6 to 8 hours. The elimination half-life of rivastigmine is very short (1-2 hours for oral and 3-4 hours for transdermal administration), but the duration of action is longer as acetylcholinesterase and butyrylcholinesterase are blocked for around 8.5 and 3.5 hours, respectively. 10 , 17 , 18

Memantine is a noncompetitive low-affinity NMDA-receptor open-channel blocker and affects glutamatergic transmission. 5 Its main elimination route is unchanged via the kidneys with a half-life of 70 hours. It has been approved by FDA for moderate and severe AD either as monotherapy or in combination with an AChEI. 3 Memantine monotherapy has demonstrated short- and long-term benefits for patients with moderate to severe AD as assessed by different scales evaluating activities of daily living, cognition, and behavioral and psychological symptoms of dementia (BPSD). 19

Memantine can be administered in combination with an AChEI, as they have complementary mechanisms of action. Their combination benefits patients with usually additive effects, without any increase in adverse effects. 14 , 15

Duration and persistence of monotherapy or combination treatment with higher doses in moderate or even in advanced dementia are associated with better global function and outcomes. 20

Medications for BPSD

Antipsychotics and antidepressants remain the main medications for BPSD. Selective serotonin reuptake inhibitors are preferred for treating depression and anxiety. Drugs with low anticholinergic effects and an acceptable tolerability, such as sertraline, citalopram, and escitalopram, are more appropriate. Antipsychotics should be administered only when a significant safety risk for the patient or for the caregivers by aggressive behaviors makes them necessary. Controversial and limited evidence cannot adequately support the use of benzodiazepines, anticonvulsants stimulants, or dextromethorphan/quinidine. Pharmacological approaches to managing BPSD are highly individualized and changeable, depending on patient’s comorbidities, stage of the disease, and symptoms’ severity. 21

Removal of superfluous and deleterious medications

Polypharmacy in older patients with dementia is usual (with a prevalence of 25%-98%). 22 Anticholinergics and sedatives are commonly used inappropriate medications. These drugs are prescribed despite strong evidence (Beers Criteria) that they should be avoided in cognitively vulnerable older persons because of their potential adverse cognitive effects. 23 Estrogen is another commonly prescribed potentially inappropriate medication despite evidence that its use is associated with increased cognitive decline in postmenopausal women. 24

Specific examples of usually prescribed potentially harmful medications in the elderly are diphenhydramine, often taken with acetaminophen for insomnia and pain, benzodiazepines for anxiety, anticholinergics (tolderodine, oxybutynin, tamsulosin) for urinary incontinence, biperiden, and pramipexole for extrapyramidal tremor 25 and sedative/hypnotics for sleep disorders. 26

Treating underlying medical conditions

Careful management of vascular risk factors (hyperlipidemia, diabetes, hypertension) is of paramount importance for patients with AD. Hydration, sleep, and nutrition status should also be closely monitored. Disorders in thyroid function or electrolytes, deficiencies in vitamin B 12 , folate, vitamin D, or systemic conditions and diseases that can affect cognition (infections, eg, urinary tract infection, pain, constipation) should be treated. 27

Current Landscape in Treatment Research for AD

No new drug has been approved by FDA for AD since 2003 and there are no approved DMTs for AD, despite many long and expensive trials. 22 , 28 As a matter of fact, more than 200 research projects in the last decade have failed or have been abandoned. 10 Nevertheless, drug pipeline for AD is still full of agents with mechanisms of action (MOA) that target either disease modification or symptoms. 4 , 10 Some of the recent failures of anti-amyloid agents in phase 3 clinical trials in patients with early-stage, mild, or mild-to-moderate stage AD were semagacestat, 29 bapineuzumab, 30 solanezumab 31 and in similar trials of β-secretase inhibitors (BACE) lanabecestat, 32 verubecestat, 33 and atabecestat. 34

The most popular and broadly accepted explanations for the multiple failures of clinical trials of DMT agents for AD include the too late starting of therapies in disease development, the inappropriate drug doses, the wrong main target of the treatment, and mainly an inadequate understanding of the pathophysiology of AD. 35 A novel approach to the problem seems more technical and mathematical than biological and suggests that the selected trials’ clinical endpoint may be extremely premature, and additionally, the variability in diagnostic markers and end points may result in inaccurate diagnosis of patients’ disease state and is finally a definite source of errors. 28 Given the fact that longer trial durations increase the probability of detecting a significant effect but at the same time increase tremendously the costs, the proposed solution seems to be the use of clinical trial simulators. 28 These simulators are constructed with mathematical, computational, and statistical tools and can predict the likelihood that a strategy and clinical end point selection of a given trial are proper or not, before the initiation of the trial. 36 They can also help in the perfecting of the design of the study; hence, they may augment the probability of success of estimated new drugs or save invaluable time and resources, by indicating earlier the forthcoming failure of any inappropriate therapy. 37 Although the use of clinical trial simulators is not frequent in recent research, 38 should this practice be abandoned, especially when potential treatments for diseases with slow progression and long duration, such as AD, are evaluated. 37

At the same time, current research remains focused on the development of therapeutic approaches to slow or stop the disease progression, taking into consideration every new aspect in the biology of the disease, the diagnostic markers, and the precise diagnosis of disease state of every individual and the design of clinical trials. Furthermore, drug development research for AD has become more complicated as preclinical and prodromal AD populations are potentially included in current trials, as well as traditionally included populations of all the clinical stages of AD dementia. 38 Consequently, current guidance provided by the FDA for AD clinical trials further includes use of fluid or neuroradiological biomarkers in disease staging for preclinical and prodromal AD trials and of a single primary outcome in prodromal AD trials. In addition, the use of clinical trial simulators, Bayesian statistics, and modifiable trial designs is strongly suggested. 4

The National Institute on Aging and the Alzheimer’s Association (NIA-AA) proposed a new framework for research, 39 which requires the application of amyloid, tau, and neurodegeneration biomarkers to clinical trials, succeeds in precise classification of patients in AD stages, and can be used to assist clinical trials design.

Tau positron emission tomography (tau PET), neurofilament light, and neurogranin are the new biomarkers that are increasingly used by clinical trials. 40

The above-mentioned biological and statistical advances that are recently integrated in clinical trials may comprise the final assets for succeeding in drug development. The current clinical trials in AD in phases 1, 2, and 3 4 , 11 - 13 are briefly discussed. The tested agents in these trials are classified either as potentially modifying the disease or as symptomatic for the cognitive enhancement, and for the relief of neuropsychiatric symptoms. The new directions in AD clinical trials, such as agents with novel MOA, advanced immunotherapies, the involvement of biomarkers in drug development, and repurposed agents, are highlighted.

A search for phases 1, 2, and 3 “recruiting” or “active but not recruiting” clinical trials for AD in clinicaltrials.gov (accessed August 19, 2019) showed 165 outcomes. The last annual review of the drug development pipeline for AD examined clinicaltrials.gov in February, 2019 (132 agents in 156 trials) and provides information and conclusions available at that time: 28 drugs in 42 clinical trials in phase 3 trials, 74 drugs in 83 phase 2 trials, and 30 drugs in 31 phase 1 trials. 4 The tested agents are classified as DMTs (73%), symptomatic cognitive enhancers (13%), and symptomatic for the treatment of BPSDs (11%). 4 The DMT agents were further separated into small molecules or biologics (monoclonal antibodies [mAbs] and other immunotherapies). The DMT agents were also classified according to their potential MOA as amyloid targeting, as tau-related targeting, and as having other MOA such as anti-inflammatory or metabolic protection, neuroprotection, and growth factor support. 4 The DMTs are suggested to be effective to delay or halt disease progression that would be expressed clinically with long-lasting benefits in cognition over many months to years. Symptomatic agents are supposed to show symptomatic benefits over weeks to many months in cognition improvement or BPSD elimination. 10

In this review, agents currently studied as potential DMTs will be discussed. Furthermore, an approach to a future “precision medicine” multifactorial therapeutic model based on biomarkers profile, genetic analysis, neuropsychologic evaluation, and neuroimaging accomplished with risk factors restriction will be attempted. 2 , 3

Currently studied DMTs for AD

Amyloid-related mechanisms—dmts.

The crucial step in AD pathogenesis is the production of amyloid (Aβ), which forms SPs (insoluble and proteolysis-resistant fibrils). The Aβ derives from a protein overexpressed in AD, APP through sequential proteolysis by β-secretase (BACE1) in the extracellular domain and γ-secretase in the transmembrane region. Full-length APP is first cleaved by α-secretase or β-secretase. The APP cleavage by α-secretase leads to nonamyloidogenic pathway, whereas APP cleavage by β-secretase (BACE1) leads to amyloidogenic pathway. Sequential cleavage of APP by BACE1 in the extracellular and γ-secretase in the transmembrane area results in the Aβ production. Major sites of γ-secretase cleavage usually occur in positions 40 and 42 of Aβ, thus Aβ40 and Aβ42 oligomers are the main products of the sequential APP cleavage, as the amyloidogenic pathway is favored in neurons because of the greater plentifulness of BACE1. On the contrary, the nonamyloidogenic processing is more favored in other cells without BACE1 predominance. 5

“Amyloid hypothesis” suggests that Aβ production in the brain triggers a cascade of pathophysiologic events leading to the clinical expression of AD. Aβ is a protein consisting of 3 main isoforms: Aβ38, Aβ40, and Aβ42. Aβ42 is the most aggregation-prone form and has the tendency to cluster into oligomers. Oligomers can form Aβ-fibrils that will eventually form amyloid plaques. Aβ40 is somewhat aggregation-prone and it is mostly found in the cerebral vasculature as a main component of “cerebral amyloid angiopathy.” Aβ40 usually constitutes more than 50% of total detected Aβ. Aβ38 is soluble, present in the vasculature of patients with sporadic and familial AD. Neurotoxicity is mainly attributed to the forming of amyloid oligomers, which finally initiates the amyloid cascade. 5

Oxidation, inflammation, excessive glutamate, and tau hyperphosphorylation are supposed to be the main pathophysiologic pillars of the cascade. Tau protein binds microtubules in cells to facilitate the neuronal transport system. Microtubules also stabilize growing axons. Hyperphosphorylated tau forms insoluble fibrils and folds into intraneuronic NFTs. Consequently, it inhibits neuronal transport and microtubule function. 2 Although in the initial amyloid hypothesis, tau hyperphosphorylation was thought to be a downstream event of Aβ deposition, it is now equally probable that tau and Aβ act in parallel pathways causing AD and enhancing each other’s toxic effects. 2 The result of massive neuronal destruction is the shortage and imbalance between neurotransmitters, such as acetylcholine, dopamine, serotonin, and to the cognitive and behavioral symptoms of AD. 5

Consequently, anti-amyloid DMTs have focused on 3 major MOAs: (1) reduction of Aβ42 production (γ-secretase inhibitors, β-secretase inhibitors, α-secretase potentiation), (2) reduction of Aβ-plaque burden (aggregation inhibitors, drugs interfering with metals), and (3) promotion of Aβ clearance (active or passive immunotherapy). 10

Reduction of Aβ42 production

γ-secretase inhibitors.

According to the amyloid hypothesis, amyloidogenic pathway is promoted after the sequential cleavage of APP by BACE1 and γ-secretase. Consequently, the inhibition of these enzymes has been considered as a major therapeutic target. Unluckily, concerning γ-secretase, in addition to APP, this particular enzyme acts on many other substances and cleaves different transmembrane proteins. Notch receptor 1, which is essential for control of normal cell differentiation and communication, is among them. 5 This fact is probably responsible for recent failures in clinical trials with γ-secretase inhibitors: semagacestat 29 was associated with worsening of activities in daily leaving and increased rates of infections and skin cancer, avagacestat 41 was associated with higher rate of cognitive decline and adverse dose-limiting effects (skin cancer) and tarenflurbil which showed low brain penetration. 42 Serious safety concerns for γ-secretase inhibitors remove γ-secretase from the role of appropriate target for the treatment of AD 43 until in depth studies on this key enzyme could help to therapeutically target γ-secretase in a safe way. 44 No γ-secretase modulators are currently studied in phase 1-3 clinical trials. 4

BACE inhibitors

Two BACE inhibitors are still elaborated: elenbecestat (E2609) in phase 2 and umibecestat (CNP520) in phase 3. 4 The later agent is studied in asymptomatic individuals at risk of developing AD (APOE4 homozygotes or APOE4 heterozygotes with elevated amyloid, detected by cerebrospinal fluid [CSF] biomarkers or amyloid PET). 45

Fluid and neuroimaging biomarkers indicative of AD pathology or neurodegeneration are integrated in this study.

However, the clinical trials with the BACE inhibitors lanabecestat, 32 verubecestat, 33 and atabecestat 34 have been recently discontinued due to unexpected difficulties. The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms). 10 , 32 - 34 All agents showed significant and dose-dependent result of reducing CSF Aβ42, but without cognitive or functional benefit while many of them were poorly tolerated and some of them failed in subjects with prodromal AD. These results might support the suggestion that blocking the process of forming of Aβ may be not capable of halting the disease progression. 46

α-secretase modulators

According to the amyloid hypothesis, nonamyloidogenic pathway is promoted after the cleavage of APP by α-secretase. Consequently, the modulation of the enzyme has been considered as a major therapeutic target. However, little is known of the main signaling pathways that could stimulate cleavage of APP by α-secretase. Restricted, nowadays, knowledge assumes that α-secretase activation is promoted through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and may be through γ-aminobutyric acid (GABA) receptor signaling; thus, agents that activate the PI3K/Akt pathway or act as selective GABA receptor modulators are suggested as potential therapeutic drugs for AD. 47 , 48

Etazolate (EHT0202) stimulates the nonamyloidogenic α-secretase pathway acting as a selective modulator of GABA receptors. A previous, phase 2 trial has showed that the agent was safe and well tolerated in patients with mild to moderate AD. However, further evaluation of etazolate in phase 3 trials has not progressed. 48 Etazolate is currently evaluated in animal studies for its preventive effect in post-traumatic stress disorder. 49

Two α-secretase modulators that activate the PI3K/Akt pathway are studied in phase 2 clinical studies: APH-1105 and ID1201. APH-1105 is delivered intranasally and is assessed in mild to moderate AD. 4 ID1201 is a fruit extract of melia toosendan and also induces α-secretase activation. It is evaluated in mild AD. 47

Reduction of Aβ-plaque burden

Aggregation inhibitors (anti-amyloid aggregation agents).

Aggregation inhibitors interact directly with the Aβ peptide to inhibit Aβ42 fiber formation, thus they are considered potential therapeutic for AD.

The last Aβ42 aggregation inhibitor which was tested in humans was the oral agent scyllo-inositol (ELND005). A phase 2 clinical trial in patients with AD did not provide evidence to support a clinical benefit of ELND005 while severe toxicity issues (infections) forced the cessation of the study. Further development of the agent at a lower dose has not progressed in the last 8 years. 50

Nowadays, specific agents in the form of peptidomimetics that inhibit and partially reverse the aggregation of Aβ 42 are tested in transmission electron microscopic studies. KLVFF is a peptide sequence that resembles the hydrophobic central part of the Aβ and gradually replaces natural polypeptides. The KLVFF compound that mainly prevents the aggregation of Aβ 42 and can also dissolve the oligomerics to a limited extend is the final compound 18, which is resilient in proteolytic decomposition. 51

Another newly developed class of peptidomimetics are the “γ-AApeptides.” 52 One of them, compound γ-AA26, seems almost 100-fold as efficient as the compound 18 of the KLVFF in the inhibition of the aggregation of Aβ 42 . 52

In vivo animal studies will be developed to manifest the biological potential of peptidomimetics.

Reduction of Aβ-plaque burden via drugs interfering with metals

Abnormal accumulation or dyshomeostasis of metal ions such as iron, copper, and zinc has been associated with the pathophysiology of AD. 5

Deferiprone is an iron chelating agent which is studied in phase 2 trials in participants with mild and prodromal AD. 4 , 53

A metal protein–attenuating compound, PBT2, has recently progressed in phase 2 AD treatment trials, as it demonstrated promising efficacy data in preclinical studies. 54 In a 3-month phase 2 study, PBT2 succeeded in a 13% reduction of CSF Aβ and an executive function improvement in a dose-related pattern in patients with early AD. 55

Promotion of Aβ clearance (active or passive immunotherapy)

The 2 main immunotherapeutic approaches that intend to promote Aβ clearance and are currently tested in clinical and preclinical studies are active and passive immunization: 56

• Active immunization.

Aβ, phosphorylated tau (ptau) peptides, or specific artificial peptides such as polymerized British amyloidosis (ABri)-related peptide (pBri) 57 are used as immunogens. ABri is a rare hereditary amyloidosis associated with a mutation that results in the production of a highly amyloidogenic protein with a unique carboxyl terminus that has no homology to any other human protein. The pBri peptide corresponds to this terminus and induces an immune response that recognizes Aβ and ptau.

Antigen-presenting cells present the immunogens to B cells. Use of Ab or ptau peptides will produce antibodies to Ab or ptau epitopes, respectively. Use of pBri will produce antibodies to both Aβ and ptau epitopes. 56

• Passive immunization.

Monoclonal Abs to Ab, ptau, or b sheet epitopes are systemically and adequately for BBB penetration infused. As antibodies cross the BBB, they act to clear, degrade, or alternatively disaggregate or neutralize their targets. 56

• Stimulation of innate immunity either by active or passive immunization also ameliorates the pathology of the disease by promoting microglia and macrophage function. 56

Overall, Aβ-targeted strategies seem promising if used very early in the progression of the disease, before the presence of any symptoms; thus, they are developed in current trials in preclinical AD. Strategies that target tau pathology, although promising, bear the risk of toxicity at the moment. Nevertheless, it is hypothesized that, in sporadic late onset AD, ptau and Aβ pathologies could be evolved by separate pathways that can affect each other synergistically. 58 Consequently, it is possible that effective AD immunotherapies must be able to simultaneously target both ptau and Aβ pathologies. 56

Immunotherapeutic approaches have dominated in the past 15 years with negative results until now. However, lessons from these fails have altered the current immunotherapy development research for AD. 56

Active Aβ immunotherapy

Six active immunotherapy agents are currently studied in phase 1, 2, and 3 clinical trials:

CAD106 is an active Aβ immunotherapeutic agent, is studied in preclinical AD under the umbrella of the Alzheimer prevention initiative generation program, which comprises 2 phase 3 studies that evaluate simultaneously the safety and efficacy of CAD106 and umibecestat in asymptomatic individuals at risk of developing AD (60-75 years of age, APOE4 homozygotes, or APOE4 heterozygotes with elevated amyloid in CSF or in amyloid PET). 45

Subjects will be registered in generation study 1 (cohort 1: CAD106 or placebo, cohort 2: umibecestat or placebo) or generation study 2 (umibecestat 50 and 15 mg, or placebo). 45

ABvac40 is evaluated in a phase 2 study, as the first active vaccine against the C-terminal end of Aβ 40 . A phase 1 study was conducted with patients with mild to moderate AD aged 50 to 85 years. Neither incident vasogenic edema nor microhemorrhages were identified. Specific anti-Aβ 40 antibodies were developed in the 92% of the individuals receiving injections of ABvac40. 59

GV1001 peptide (tertomotide) was previously studied as a vaccine against various cancers, whereas now it is evaluated in a phase 2 study for AD. 60

ACC-001 (vanutide cridificar), an Aβ vaccine, was studied in phase 2a extension studies in subjects with mild to moderate AD. It was administered with QS-21 adjuvant. Long-term therapy with this combination was very well tolerated and produced the highest anti-Aβ IgG titers compared with other regimens. 61

UB-311, a synthetic peptide used as Aβ vaccine, has been advanced into an ongoing phase 2 study in patients with mild and moderate AD. In phase 1, it induced a 100% responder rate in patients with AD. The usual adverse effects were swelling in the injection site and agitation. A slower cognitive decline rate was observed in patients with mild AD. 62

Lu AF20513 epitope vaccine is estimated in a phase 1 study in mild AD. 63

The occurrence of encephalitis in previous studies (AN-1792) 64 led to the development of improved anti-Aβ active immunotherapy agents, more specific to Aβ sites less probable to activate T cells, currently studied in clinical trials. 5 , 6

Passive Aβ immunotherapy—via mAbs

Passive Ab immunotherapy via mAbs is the most active and promising class. Cerebral microhemorrhages and vasogenic edema are the main drawbacks in this group of agents. 5 Valuable learning gained from previous failed phase 3 trials of the first agents of this class, bapineuzumab 65 and solanezumab, 66 enlightened the mAbs’ research. Strict inclusion criteria were applied, such as biomarker proof of “amyloid positivity” and enrollment of individuals with preclinical stages of the disease. Furthermore, the design of the studies became more specific and targeted: the characteristics of amyloid-related imaging abnormalities were associated with the dose of antibodies and APOε4 genotyping, higher dosing necessity was recognized, and accurate measures for specific targets, such as reduction of Aβ plaque burden on amyloid PET, were required. 10

Many ongoing mAbs trials are in phase 3, including aducanumab, 67 gantenerumab, 68 and BAN2401 69 in prodromal and very mild AD, and crenezumab, 70 gantenerumab, and solanezumab 71 in studies for preclinical or at-risk populations. First results from aducanumab and BAN2401 trials suggested, at first, a treatment-related result of reducing in cerebral amyloid burden in agreement to deceleration of cognitive decline in patients with prodromal and very mild AD. 71 , 72 On the contrary, the initial trial of gantenerumab in prodromal AD was prematurely stopped for lack of efficacy, but exploratory analyses suggest that higher dosing of gantenerumab may be needed for clinical efficacy and an open-label extension for participating patients with mild AD is continued, simultaneously with a double-blind, placebo-controlled study in patients with mild AD. 4 , 68 Similarly, until now, solanezumab did not delay rates of brain atrophy. 73

Intravenous doses of LY3002813 (donanemab) and LY3372993 are studied in participants with mild cognitive impairment (MCI) and mild to moderate AD in separate phase 1 clinical studies. 4

Passive Aβ immunotherapy—via immunoglobulins

Anti-Aβ antibodies are included in naturally occurring autoantibodies. In contrast to mAbs, blood-derived human anti-Aβ immunoglobulin G (IgG) Abs are polyclonal, with lower avidity for single Aβ molecules, and higher for a broader range of epitopes, especially in Aβ oligomers and fibrils. The natural presence of antibodies against Aβ has been reported in intravenous immunoglobulin (IVIg); thus, IVIg has been considered as a possible AD treatment. Intravenous immunoglobulin is obtained from plasma of healthy donors and is made up of human Abs mainly of the IgG-type. 5 , 74

Nevertheless, the first completed phase 3 trial of IVIg as a treatment for AD demonstrated good tolerability but lack of efficacy of the agent on clinical stability or delay of cognitive or functional decline of participants with mild and moderate AD. 74

Another strategy directed at diminishing the accumulation of Aβ in the brain is based in altering the transportation of Aβ through the BBB. A recent therapeutic method performs plasma exchange (PE) with albumin replacement, inducing the shifting of the existing dynamic equilibrium between plasma and brain Aβ. This therapeutic method is based in the following considerations: (1) high levels of Aβ aggregation in the brain are accompanied by low levels of Aβ in CSF in AD, (2) albumin is the main protein transporter in humans, (3) albumin binds around the 90% of the circulating Aβ, and (4) albumin has proved Aβ-binding ability. Consequently, it is suggested that PE-mediated possession of albumin-bound Aβ would increase the shift of free Aβ from CSF to plasma to correct the imbalance between brain and blood Aβ levels. 75

A phase 3 trial called Alzheimer’s Management by Albumin Replacement (AMBAR) in mild and moderate AD assesses PE with several replacement volumes of albumin, with or without intravenous immunoglobulin. 76

Furthermore, an ongoing phase 2 study evaluates IVIg Octagram 10% in mild and moderate AD. 4

A novel immunotherapeutic strategy that targets simultaneously Aβ and tau is represented by the NPT088 agent. NPT088 is a mixture of the capsid protein of bacteriophage M13 (g3p) and human-IgG 1 -Fc. NPT088 reduced Aβ and ptau aggregates and improved cognition in aged Tg2576 mice. The agent is currently assessed in a phase 1 clinical study. 77

Tau-related mechanisms—DMTs

Anti-phospho-tau approaches consist a major potential treatment strategy, even if there are yet no agents with this specific MOA advanced in phase 3 studies.

Only 1 agent with tau-related mechanism is evaluated in phase 2/3, whereas 10 agents that target tau as one of their mechanisms are evaluated in phase 2, and 5 more agents with tau-related mechanism are assessed in phase 1 studies. 4

Prevention of ptau formation

The hyperphosphorylation of tau is induced by kinases. 78 Thus, kinase inhibitors are examined as potential therapeutic approaches targeting tau. Glycogen synthase kinase 3 (GSK3β) has become prominent as a possible therapeutic target. The most studied GSK3 inhibitor is lithium chloride, a therapeutic agent for affective disorders, which seems to prevent phosphorylation of tau in mouse models. Lithium is currently reassessed within the novel framework for drug research. 79

Another GSK-3 inhibitor, tideglusib, did not meet phase 2 clinical endpoints in patients with mild and moderate AD. 80

ANAVEX 2-73 is evaluated in a phase 2 trial, for eligible subjects AD MCI or mild AD. 81 ANAVEX 2-73 is also a GSK-3b inhibitor but additionally it is a high affinity sigma 1 receptor agonist and a low-affinity muscarinic agonist. 4 Results presented at 2019 Alzheimer’s Association International Conference (AAIC) revealed that patients treated with ANAVEX 2-73 had high levels of 2 gut microbiota families, Ruminococcaceae and Porphyromonadaceae, which were associated with improved activities of daily living. The effect might potentially be reversal of the microbiota imbalances and might have a homeostatic effect on the brain-gut-microbiota axis. 81

Inhibitors of tau aggregation

Methylene blue (MB), a known phenothiazine, is evaluated in AD studies as a potential tau aggregation inhibitor. The problem with this drug is that urine is colored blue, resulting in a lack of blinding. A monotherapy trial with MB on mild and moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT00515333","term_id":"NCT00515333"}} NCT00515333 ) has demonstrated some clinical benefit in moderate, but not mild AD. 82 However, the methodology of the study, as blinding is impossible, has been highly criticized. 83

Methylene blue’s derivative TRx0237 (LMTX) which was studied in phase 3 failed finally to show efficacy, and based on the analysis of the results, a new phase 2/3 study named LUCIDITY was started 1 year ago in subjects with mild AD with a lower dose of the agent. 84

Microtubule stabilizers

The microtubule-stabilizing agent davunetide was studied in a phase 2 trial but it did not meet the clinical end points. 85

TPI-287 (abeotaxane), a small molecule derived from taxol, is a microtubule protein modulator. It was administered intravenously to patients with mild to moderate AD in a phase 1/2 study ( {"type":"clinical-trial","attrs":{"text":"NCT01966666","term_id":"NCT01966666"}} NCT01966666 ). First results presented report that the agent was not well tolerated by the participants. 84

IONIS MAPTRx (BIIB080), a microtubule-associated protein tau RNA inhibitor, an antisense oligonucleotide, is assessed in a phase 2 clinical study that is still in the recruiting process of patients with mild AD ( {"type":"clinical-trial","attrs":{"text":"NCT02623699","term_id":"NCT02623699"}} NCT02623699 ). 86

Targeting posttranslational modifications of Tau

Another tau modification that promotes aggregation besides phosphorylation is posttranslational modification by lysine acetylation. Thus, the use of inhibitors of tau acetylation is proposed as a possible therapeutic approach for AD.

Nilotinib is a c-Abl tyrosine kinase inhibitor which is used in patients with leukemia. It also appears to trigger intraneuronal autophagy to clear tau. It is now studied in a phase 2 trial in individuals with mild to moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT02947893","term_id":"NCT02947893"}} NCT02947893 ). 4 , 83

Promotion of Tau clearance—immunotherapy

Recently emerged evidence in various animal models strongly suggests that targeting ptau epitopes is a practical approach to induce antibody responses that are able to promote tau clearance. 81 Hence, a number of active and passive immunotherapy projects have reached clinical trials for AD treatment. 83

Active immunotherapy

AADvac1 contains a synthetic tau peptide and is currently studied in a phase 2 clinical study in mild to moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT02579252","term_id":"NCT02579252"}} NCT02579252 ). 4 , 10 , 83

Passive immunotherapy

ABBV-8E12 is a humanized anti-tau MAb assessed in a phase 2 clinical study in patients with early AD ( {"type":"clinical-trial","attrs":{"text":"NCT02880956","term_id":"NCT02880956"}} NCT02880956 ). 87

BIIB092 is a humanized IgG4 MAb against tau fragments derived from the stem cells of a patient with familial AD. 84 A phase 2 clinical trial assesses the safety and efficacy of the agent in participants with AD MCI and mild AD. 4

RO7105705 (MTAU9937 A) is an anti-tau MAb which is assessed in a phase 2 study in individuals with prodromal and mild AD ( {"type":"clinical-trial","attrs":{"text":"NCT03289143","term_id":"NCT03289143"}} NCT03289143 ). 83 , 88

Three other anti-tau mAbs (BIIB076, JNJ-63733657, and LY3303560) are currently assessed in phase 1 clinical trials. 4

DMTs with other mechanisms

Neuroprotection.

AGB101 (low-dose extended-release levetiracetam) is an SV2A modulator that is assessed in a phase 3 clinical trial as a repurposed agent (approved for use in another indication, not epilepsy but MCI due to AD). It is supposed to reduce neuronal hyperactivity induced by Aβ ( {"type":"clinical-trial","attrs":{"text":"NCT03486938","term_id":"NCT03486938"}} NCT03486938 ) ( Diagram 1 ). 4

DMTs with other mechanisms. DMTs indicate disease-modifying therapies; hMSCs, human mesenchymal stem cells.

BHV4157 (troriluzole) is a glutamate modulator that reduces synaptic levels of glutamate and is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03605667","term_id":"NCT03605667"}} NCT03605667 ). 4

Icosapent ethyl is the eicosapentaenoic acid (EPA) omega-3 fatty acid in a purified form. It is supposed to protect neurons from disease pathology and is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02719327","term_id":"NCT02719327"}} NCT02719327 ). 4

There are also 2 biologics and 24 small molecules with neuroprotection as one of their mechanisms 4 assessed in phase 2 clinical studies and 8 small molecules in phase 1 clinical trials. 4

Anti-inflammatory effects

Although neuroinflammation has been proposed as a possible mechanism for the pathogenesis of AD more than 30 years ago, only recently research is spurred into neuroiflammation probably due to 2 enlightening discoveries: first, there is evidence that activated glial cells are involved in the formation of the brain lesions in AD and second, epidemiological studies revealed that patients with rheumatoid arthritis, who are treated with anti-inflammatory drugs for decades, are spared from AD. 89 Further exploration of the inflammatory mechanisms in the disease showed that activation of glial cells, microglia, and astrocytes induces the production of inflammatory cytokines, mainly interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α). More specifically, TNF-α signaling has been proved to exacerbate both Aβ aggregation and tau phosphorylation in vivo, 90 whereas its levels have been found elevated in brain and plasma of patients with AD. 91

According to the previously mentioned neuroinflammatory mechanisms, it is established by multiple biomarker and epidemiological studies of Aβ levels in the CSF and the brain that nonsteroidal anti-inflammatory drugs, complement activation blockers, and other anti-inflammatory agents could postpone the clinical onset of AD if they are timely and for a long time applied, such as in rheumatoid arthritis. 89

Furthermore, the already existing TNF-α inhibitors (TNFIs), which are FDA-approved biologic drugs (mAbs) for the treatment of rheumatoid arthritis, Crohn disease, psoriatic arthritis, and other peripheral inflammatory diseases, are studied as a potential therapeutic strategy for AD. The TNF-α–specific mAbs are the agents infliximab, adalimumab, golimumab, and certolizumab, whereas etanercept is a recombinant fusion protein, which is also a TNFI. 91 The limited BBB penetration of these agents is the main drawback for their development. Peripheral targeting of TNF-α activity is the one proposed method for the tackling of the problem and reengineering of the TNFIs to enable BBB penetration is the other. 91 To sum up, large-scale randomized controlled trials assessing the safety and the effectiveness of TNFIs on patients with AD are warranted.

The following are the anti-inflammatory agents currently assessed in phase 3 clinical trials:

• ALZT-OP1a plus ALZT-OP1b (cromolyn plus ibuprofen) is a combination of a mast cell stabilizer and an anti-inflammatory agent, respectively, assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02547818","term_id":"NCT02547818"}} NCT02547818 ). 4
• COR388 targets a periodontal pathogen acting as bacterial protease inhibitor that reduces neuroinflammation and consequently hippocampal degeneration and is currently assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03823404","term_id":"NCT03823404"}} NCT03823404 ). 4
• Masitinib acts on mast cells as a selective tyrosine kinase inhibitor and a modulator of neuroinflammation. It is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT01872598","term_id":"NCT01872598"}} NCT01872598 ). 4

The following are the anti-inflammatory agents studied in phase 2:

• Elderberry Juice improves the mitochondrial function acting as powerful antioxidant rich in anthocyanins ( {"type":"clinical-trial","attrs":{"text":"NCT02414607","term_id":"NCT02414607"}} NCT02414607 ) and GRF6019, a human plasma protein fraction administered with infusions, based on the hypothesis that brain neuroinflammation can be counteracted by young blood parabiosis ( {"type":"clinical-trial","attrs":{"text":"NCT03520998","term_id":"NCT03520998"}} NCT03520998 , {"type":"clinical-trial","attrs":{"text":"NCT03765762","term_id":"NCT03765762"}} NCT03765762 ). 4
• Anti-inflammatory agents studied in phase 1 are the mAbs AL002, AL003 ( {"type":"clinical-trial","attrs":{"text":"NCT03635047","term_id":"NCT03635047"}} NCT03635047 , {"type":"clinical-trial","attrs":{"text":"NCT03822208","term_id":"NCT03822208"}} NCT03822208 ). 4

Growth factor promotion

NDX-1017 is an hepatocyte growth factor with the role to regenerate neurons, which is studied in a phase 1 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03298672","term_id":"NCT03298672"}} NCT03298672 ). 4

Metabolic effects

Losartan plus amlodipine plus atorvastatin plus exercise is a combination repurposed agent suggested to succeed significant reduction of the vascular risk capable of preserving cognitive function. It is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02913664","term_id":"NCT02913664"}} NCT02913664 ). 4

Candesartan, an angiotensin receptor blocker; formoterol, a β 2 adrenergic receptor agonist; and intranasal insulin glulisine, which rises brain insulin signaling, are currently studied in phase 2 clinical trials ( {"type":"clinical-trial","attrs":{"text":"NCT02646982","term_id":"NCT02646982"}} NCT02646982 , {"type":"clinical-trial","attrs":{"text":"NCT02500784","term_id":"NCT02500784"}} NCT02500784 , {"type":"clinical-trial","attrs":{"text":"NCT02503501","term_id":"NCT02503501"}} NCT02503501 , respectively), whereas intranasal insulin aspart is assessed in a phase 1 clinical study. 4

Stem cell therapies

AstroStem is a stem-cell-based treatment administered 10 times intravenously, which consists of stem cells derived from autologous adipose tissue. AstroStem is currently assessed in a phase 2 study ( {"type":"clinical-trial","attrs":{"text":"NCT03117738","term_id":"NCT03117738"}} NCT03117738 ), whereas hMSCs (human mesenchymal stem cells) treatment is assessed in a phase 1 study ( {"type":"clinical-trial","attrs":{"text":"NCT02600130","term_id":"NCT02600130"}} NCT02600130 ). 4

Symptomatic agents

Symptomatic treatments are agents that target and improve the clinical symptoms of the disease, either cognitive or BPSD, without modifying the pathological steps leading to AD or acting on the evolution of the disease, as DMTs are supposed to do.

Overall, there are 33 symptomatic agents in current trials: 19 agents aim to improve cognition and 14 target BPSD.

Eleven of them are studied in phase 3: 3 cognitive intensifiers and 8 acting on BPSD.

Twenty symptomatic agents are in phase 2: 14 cognitive intensifiers and 6 acting on BPSD.

There are also 2 cognitive intensifiers being studied in phase 1. 4

Arduous research efforts persist to develop effective DMTs for AD, as well as symptomatic therapeutics. A plethora of continuing phase 1, 2, and 3 human studies are focused on various treatment targets in AD. Given the recent experience of a high proportion of lack of success in AD clinical trials on therapeutic agents, more recent trials appear robustly empowered by the integration of developments in biomarkers of AD, of the targeting of a single primary outcome, especially in prodromal AD studies, of the enrollment of earlier populations and the innovative trial designs. 91 - 93

At the same time, innovative research targets the development of more sophisticated diagnostic tools (neuroimaging, fluid, proteomic, and genomic AD biomarkers), whereas prevention studies for the disease are also ongoing. 10

If all these research efforts come to fruition, an effective “precision medicine” context could be applied in every patient with AD in the near future: risk factor elimination, comorbid disease treatment, and personalized advice for lifestyle modification will be provided. An AD biomarkers and neuropsychological evaluation profile will be outlined. Afterward, the patient may start a combination of DMTs tailored to meet his genetic, neuroimaging, biochemical, and neuropsychological requirements. 3 , 94

Furthermore and beyond any DMT perspective, clinicians should always maintain a patient/caregiver-targeted dealing with AD. Establishing a strong therapeutic alliance with the patient and his or her caregivers with a holistic and realistic approach involving psychoeducation, behavioral, and environmental techniques; advanced planning for future care needs; and appropriate pharmaceutical treatment is not only an efficient but also an ethical care in AD.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions: SGP conceptualized the study, developed the proposal and coordinated the project. KGY completed initial data entry and analysis, and wrote the report. Both authors read and approved the final manuscript.

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• A new drug, lecanemab, has been shown to reduce the decline in memory and thinking associated with Alzheimer's.
• As populations age, dementia cases are on the rise, with 10 million new people diagnosed each year.
• Dementia is a collective term for a group of diseases or brain injuries that can lead to a change in cognitive functioning as well as other symptoms like lack of emotional control.

It is one of the biggest diseases of our time: 10 million new cases of dementia are diagnosed every year, according to the World Health Organization (WHO). More than 55 million people worldwide live with a form of dementia and it is the seventh leading cause of death among all diseases.

Now a new drug is offering a glimmer of hope after years of searching for a treatment. In clinical trials, lecanemab has been shown to slow the cognitive decline associated with the disease. The drug attacks the protein clumps in the brain that many think are the cause of the disease.

Although dementia patients are currently offered drugs, none of them affect the progression of the disease which is why scientists in the field are so excited about this latest development. Alzheimer's Research UK called the findings "a major step forwards" .

But while this is undoubtedly positive news, the body also points out that the benefits of the drug were small and came with significant side effects. In addition, lecanemab has been proven to work in the early stages of the disease, so would rely on doctors spotting it before it had progressed too far.

With the number of dementia cases expected to rise to 78 million by 2030 and 139 million in 2050, according to the WHO, the race is on for scientific developments and research that will help us understand, treat and possibly prevent the disease.

A global impact

As populations age, the number of cases of dementia rises. While the deterioration of cognitive functioning is not caused by age itself, it does primarily affect the older generation. For many elderly people it also results in disability and loss of independence - which can have psychological, social and economic implications for them and their families, carers and society more broadly.

The estimated global cost of dementia to society was placed at $1.3 trillion in 2019, and is expected to rise to $2.8 trillion by 2030, WHO says.

Alzheimer’s Diesease, a result of rapid ageing that causes dementia, is a growing concern. Dementia, the seventh leading cause of death worldwide, cost the world $1.25 trillion in 2018, and affected about 50 million people in 2019. Without major breakthroughs, the number of people affected will triple by 2050, to 152 million.

To catalyse the fight against Alzheimer's, the World Economic Forum is partnering with the Global CEO Initiative (CEOi) to form a coalition of public and private stakeholders – including pharmaceutical manufacturers, biotech companies, governments, international organizations, foundations and research agencies.

The initiative aims to advance pre-clinical research to advance the understanding of the disease, attract more capital by lowering the risks to investment in biomarkers, develop standing clinical trial platforms, and advance healthcare system readiness in the fields of detection, diagnosis, infrastructure and access.

What is dementia?

Dementia is a collective term for a group of diseases or injuries which primarily or secondarily affect the brain. Alzheimer’s is the most common of these and accounts for around 60-70% of cases. Other types include vascular dementia , dementia with Lewy bodies (abnormal protein clumps) and a group of diseases that contribute to frontotemporal dementia. It can also be triggered by strokes, excessive use of alcohol, repetitive head injuries, nutritional deficiencies, or follow some infections like HIV, the Alzheimer’s Society explains.

The different forms of dementia can often be indistinct and can co-exist.

Different people are affected in different ways, depending on the underlying cause. But the syndrome is usually progressive and can affect a range of functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement.

Changes in mood and ability to control emotions often accompany these cognitive variations.

Can it be treated?

There is no cure for dementia, although there are numerous treatments being worked on and at clinical trial phase. Dementia care currently focuses on early diagnosis, optimizing health and wellbeing and providing long-term support to carers.

Besides age, there are a number of other risk factors, which if avoided, can decrease the chances of dementia and slow its progression. Preventative steps include being physically active, not smoking, avoiding the harmful use of alcohol, as well as maintaining a healthy diet, weight, blood pressure, cholesterol and blood sugar levels.

Other risk factors associated with dementia include depression, social isolation, low educational attainment, cognitive inactivity and even air pollution .

What is the impact?

People with dementia rely heavily on informal care - i.e., friends and family. These carers spent on average five hours a day looking after people living with dementia in 2019, according to WHO figures. Informal care is thought to cover half of the overall financial burden of dementia.

There is also a disproportionate impact on women. They account for 65% of all dementia-related deaths, and also have a greater number of years affected by the disease. Women also typically provide the majority of informal care - covering over two-thirds of the carer hours for people living with dementia.

What are the latest developments?

The fact that dementia is only diagnosed once symptoms appear means that by the time people take part in clinical trials the disease is often quite well advanced. This can hamper the development of drugs. However, research analyzing data from the UK Biobank has indicated there are a collection of signals that could indicate a problem years before dementia is currently being diagnosed .

Other scientists postulate that, rather than being a disease of the brain, Alzheimer’s is in fact a disorder of the immune system within the brain . They believe research should instead focus on drugs targeting auto-immune pathways .

On a less positive note, researchers found that people who have recently received a dementia diagnosis, or diagnosed with the condition at a younger age, are at an increased risk of suicide . This underlines the importance of a strong support network, particularly among those newly diagnosed.

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Here Are the New Drugs and Treatments We Could See in 2024

2023 was a strong year for innovative new drugs, with new medications for Alzheimer’s disease , weight loss , and the first treatment based on the gene-editing technology CRISPR .

But 2024 is also shaping up to be a milestone year for some exciting therapies. Here's what to expect.

Another new Alzheimer's drug

Eli Lilly could debut a new treatment for Alzheimer’s disease that targets amyloid, the protein that builds up in the brains of patients. In studies that the company has submitted to the U.S. Food and Drug Administration (FDA) for approval, people receiving the drug experienced 35% slower cognitive decline according to cognitive tests than those getting placebo, and 40% less decline in their ability to perform daily activities such as driving or holding conversations. That’s a slightly higher efficacy than the existing medications for the neurodegenerative disease, and experts are hoping that if patients start taking it early enough, they might be able to hold off the worst effects of memory loss and cognitive decline for a few years. The FDA is expected to make a decision about the drug in early 2024.

Innovative blood-disorder treatments

After approving the first CRISPR treatment, Casgevy, for sickle cell anemia, the FDA is reviewing the same therapy for another genetic blood disorder called beta thalassemia. In both conditions, people have abnormal blood cells that can’t carry enough oxygen, which leads to painful attacks and frequent blood transfusions and hospitalizations. The gene-editing therapy is a one-time treatment that allows people to make more healthy blood cells, which can reduce the number of painful episodes. U.K. health authorities have granted Casgevy conditional marketing authorization, and the FDA is expected to decide in March whether to approve the treatment for beta thalassemia.

The agency is also considering other gene-based treatments that don’t use CRISPR but rely on more traditional virus-based methods. One is for hemophilia B. Patients with the condition experience moderate-to-severe bleeding episodes because they lack a coagulation factor that the gene therapy provides. In studies by the manufacturer, Pfizer, the therapy lowered the risk of annual bleeding among a few dozen men who tested it by 71% . The FDA is expected to make a decision about the treatment in the second quarter of 2024.

More From TIME

A novel schizophrenia drug.

Later in the year, the FDA will review a new drug treatment for schizophrenia —the first for the psychiatric condition in decades. Karuna Therapeutics has improved upon existing antipsychotics by targeting a different brain chemical than existing medications, which focus on dopamine. In a study of a couple hundred people with schizophrenia, the drug, which works on the muscarinic receptors in the brain involved in regulating positive and negative thoughts, helped to reduce the extremes of symptoms that are typical of the condition. If approved, the drug could help more people with schizophrenia relieve their worst symptoms, since many people stop taking the existing medications because of their side effects.

New year, same old questions of access

As exciting as the possible new medications are, they also raise questions about affordability and accessibility . Innovative drug treatments involving gene therapy and CRISPR, for example, are designed to be one-time treatments that can mitigate the need for repeated and often lifelong medical care. But that means higher upfront costs, and it’s not clear whether insurers will cover such hefty price tags.

As more therapies reach the market, however, they could change the reimbursement structure as insurers will likely feel increasing pressure to cover treatments that could be not just life-changing but also potentially curative—and save millions in long-term health care costs.

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New breakthroughs on Alzheimer’s

MIT scientists have pinpointed the first brain cells to show signs of neurodegeneration in the disorder and identified a peptide that holds potential as a treatment.

• Anne Trafton archive page

Neuronal hyperactivity and the gradual loss of neuron function are key features of Alzheimer’s disease. Now researchers led by Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, have identified the cells most susceptible to this damage, suggesting a good target for treatment. Even more exciting, Tsai and her colleagues have found a way to reverse neurodegeneration and other symptoms by interfering with an enzyme that is typically overactive in the brains of Alzheimer’s patients. 

In one study , the researchers used single-­cell RNA sequencing to distinguish two populations of neurons in the mammillary bodies, a pair of structures in the hypothalamus that play a role in memory and are affected early in the disease. Previous work by Tsai’s lab found that they had the highest density of amyloid beta plaques, abnormal clumps of protein that are thought to cause many Alzheimer’s symptoms. 

The researchers found that neurons in the lateral mammillary body showed much more hyperactivity and degeneration than those in the larger medial mamillary body. They also found that this damage led to memory impairments in mice and that they could reverse those impairments with a drug used to treat epilepsy.

In the other study , the researchers treated mice with a peptide that blocks a hyperactive version of an enzyme called CDK5, which plays an important role in development of the central nervous system. They found dramatic reductions in neurodegeneration and DNA damage in the brain, and the mice got better at tasks such as learning to navigate a water maze.

CDK5 is activated by a smaller protein known as P35, allowing it to add a phosphate molecule to its targets. However, in Alzheimer’s and other neurodegenerative diseases, P35 breaks down into a smaller protein called P25, which allows CDK5 to phosphorylate other molecules—including the Tau protein, leading to the Tau tangles that are another characteristic of Alzheimer’s.

Pharmaceutical companies have tried to target P25 with small-molecule drugs, but these drugs also interfere with other essential enzymes. The MIT team instead used a peptide—a string of amino acids, in this case a sequence matching that of a CDK5 segment that is critical to binding P25.

In tests on neurons in a lab dish, the researchers found that treatment with the peptide moderately reduced CDK5 activity. But in a mouse model that has hyperactive CDK5, they saw myriad beneficial effects, including reductions in DNA damage, neural inflammation, and neuron loss. 

The treatment also produced dramatic improvements in a different mouse model of Alzheimer’s, which has a mutant form of the Tau protein. Tsai hypothesizes that the peptide might confer resilience to cognitive impairment in the brains of people with Tau tangles.

“We found that the effect of this peptide is just remarkable,” she says. “We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits.”

The researchers hope the peptide could eventually be used as a treatment not only for Alzheimer’s but for frontotemporal dementia, HIV-induced dementia, diabetes-­linked cognitive impairment, and other conditions. 

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Most popular, large language models can do jaw-dropping things. but nobody knows exactly why..

And that's a problem. Figuring it out is one of the biggest scientific puzzles of our time and a crucial step towards controlling more powerful future models.

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OpenAI teases an amazing new generative video model called Sora

The firm is sharing Sora with a small group of safety testers but the rest of us will have to wait to learn more.

Google’s Gemini is now in everything. Here’s how you can try it out.

Gmail, Docs, and more will now come with Gemini baked in. But Europeans will have to wait before they can download the app.

The problem with plug-in hybrids? Their drivers.

Plug-in hybrids are often sold as a transition to EVs, but new data from Europe shows we’re still underestimating the emissions they produce.

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New 20-minute non-invasive treatment could reverse memory loss, study says

More than 747,000 Canadians currently live with Alzheimer's and other forms of dementia, but a new study suggests age-related memory loss could be reversed with a 20-minute non-invasive treatment.

Researchers from Boston University outlined their findings in a paper published in Nature Neuroscience last week . Their treatment involves a wearable cap equipped with electrodes that sends electrical signals into the brain, and researchers say this could help improve memory function.

"An increasingly older population leads to additional personal, social, healthcare and economic costs. A factor greatly contributing to these costs is the impairment in basic memory systems essential for activities of everyday life, such as making financial decisions or understanding language," lead researcher Robert Reinhart said in a news release published Monday.

In the study, patients received electrical brain stimulation for 20 minutes for four consecutive days. Each day, the patients were given a list of 20 words and were asked to memorize and immediately recite the words.

Two different treatment methods were tested: one targeting short-term memory with low-frequency stimulation and another for improving long-term memory with high-frequency stimulation in the brain's prefrontal cortex. Both methods were tested against a placebo in a randomized double-blind trial.

The researchers found that after three or four days of applying low-frequency electrical signals to the brain, patients exhibited better short-term memory, and the improvements remained a month later.

Sending high-frequency signals into the brain improved long-term memory after Day 2, as well as after a month. The researchers also found that individuals that had lower cognitive function had larger and longer-lasting memory improvement as a result of the treatment.

"Clinically, this is important because there are people with only short-term memory problems and others with only long-term memory problems. So, having tools in hand that can address each of these memory systems is of great value," Reinhart said.

In a 2019 study led by Reinhart's team, the researchers had applied the electrode treatment for one 25-minute session, but patients only exhibited memory benefits for less than an hour before the improvements vanished. However, Reinhart's treatment now applies electrical stimulation for multiple days.

"In this new study, we used multiple, consecutive days of stimulation for 20 minutes to cause long-lasting memory improvements that lasted one month. Previously, the effects lasted only 50 minutes," Reinhart said.

Currently, Reinhart notes that the existing treatment options for age-related impaired cognition produce mixed results and come with several risks and side effects.

"For those reasons, there’s an urgent need to develop innovative therapeutic interventions that can provide rapid and sustainable improvements with minimal side effects," he said. 

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• Winter 2024 | VOL. 36, NO. 1 CURRENT ISSUE pp.A5-81

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Advances in Treatment of Frontotemporal Dementia

• Nahuel Magrath Guimet , M.D. ,
• Lina M. Zapata-Restrepo , M.D. ,
• Bruce L. Miller , M.D.

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In this review, the authors explored the clinical features of frontotemporal dementia (FTD), focusing on treatment. The clinical features of FTD are unique, with disinhibition, apathy, loss of empathy, and compulsions common. Motor changes occur later in the illness. The two major proteins that aggregate in the brain with FTD are tau and TDP-43, whereas a minority of patients aggregate FET proteins, primarily the FUS protein. Genetic causes include mutations in MAPT , GRN , and C9orf72 . There are no medications that can slow FTD progression, although new therapies for the genetic forms of FTD are moving into clinical trials. Once a diagnosis is made, therapies should begin, focusing on the family and the patient. In the setting of FTD, families experience a severe burden associated with caregiving, and the clinician should focus on alleviating this burden. Advice around legal and financial issues is usually helpful. Careful consideration of environmental changes to cope with abnormal behaviors is essential. Most compounds that have been used to treat dementia of the Alzheimer’s disease type are not effective in FTD, and cholinesterase inhibitors and memantine should be avoided. Although the data are scant, there is some evidence that antidepressants and second-generation antipsychotics may help individual patients.

Frontotemporal dementia (FTD) refers to a group of neurodegenerative brain disorders characterized by atrophy of the frontal and anterior temporal lobes ( 1 ) and is one of the most common forms of early-onset dementia ( 2 ). Clinically, there are three main syndromes of FTD that are generally recognized on the basis of their clinical presentations: a behavioral variant FTD (bvFTD) characterized by a progressive deterioration of personality, social comportment and cognition ( 3 ); and two language presentations, classified under primary progressive aphasia (PPA), in which an insidious decline in language skills is the primary feature ( 1 ). These PPAs are divided on the basis of the pattern of language breakdown into a nonfluent variant of aphasia (nfvPPA) and a semantic variant (svPPA). A third form of PPA, the logopenic variant (lvPPA), usually occurs in association with the pathology of Alzheimer’s disease but can also be found in relation to FTD ( 4 ). There are forms of the disease that escape the descriptions of the main syndromes in FTD; an example of this is the right temporal variant, which is often associated with semantic memory impairment, prosopagnosia, and behavioral symptoms often associated with a socioemotional deficit ( 5 ). These syndromes have specific clinical symptoms and neuroimaging and pathological characteristics, although considerable heterogeneity and overlap exist in clinical practice, particularly as the disease progresses ( 1 ). In this article, pharmacological and nonpharmacological treatments for the neuropsychiatric aspects of FTD are reviewed. Promising advances in molecule-based therapies for the genetic forms are highlighted.

NEUROPATHOLOGY

Frontotemporal lobar degeneration (FTLD) is the term used to refer to a group of progressive brain diseases that predominantly affect the frontal and anterior temporal lobes. Thus, FTLDs include the clinical syndromes that are part of FTD: bvFTD, nfvPPA, and svPPA and also include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and bvFTD with motor neuron disease (FTD-MND). These diseases, although sharing similar anatomy, have diverse etiologic causes at the neuropathological and genetic levels. Pathologically, FTLD is subdivided according to the composition of the abnormal inclusions of misfolded proteins. There are three main subgroups: FTLD-tau, FTLD-TDP, and FTLD-FET. The first two, characterized by the accumulation of tau protein and TDP-43, account for 90%−95% of FTLD cases; the third, a consequence of FET protein accumulation, is related to the remaining 5%−10% of cases ( 6 ).

Tau is a microtubule-associated protein that has been linked to multiple molecular processes, including synaptic plasticity, cell signaling, and regulation of axonal stability ( 7 ). There are six isoforms of tau expressed in the brain from alternative mRNA splicing of a single gene, MAPT . What separates the longer forms of tau from the shorter forms is the inclusion (or exclusion) of the 31 amino acids encoded in exon 10 at the carboxy-terminal end into three isoforms with four repeats (4R forms) and their exclusion into three isoforms with three repeats (3R forms) ( 8 ). The expression of tau is regulated throughout development, and in the adult brain, all six tau isoforms are present, with equal numbers of 3R and 4R forms. In Pick’s disease, we mainly find 3R forms, whereas 4R forms can be related to PSP, CBD, nfvPPA, and other pathologies such as globular glial tauopathy (GGT); mixed 3R-4R forms can be found in Alzheimer’s disease (AD) and chronic traumatic encephalopathy ( 9 ). In addition, the tau protein undergoes posttranslational changes, the most commonly described being phosphorylation, which can modify the affinity of tau for microtubules and lead to self-aggregation. There are 85 known putative phosphorylation sites ( 7 ), and tau posttranslational modifications characterize disease heterogeneity and stage in dementia ( 10 ).

FTLD-TDP is characterized by the accumulation of 43-kDa transactive response DNA binding protein (TDP-43), a multifunctional nucleic-acid-binding protein related to RNA metabolism to which other functions such as neurite outgrowth and axonal repair after injury have been attributed ( 11 ). TDP-43 loss from the nucleus leads to the up- and downregulation of more than 100 different proteins, including stathmin-2 ( 12 ). Upregulation of stathmin-2 is a proposed therapy for FTLD-TDP. In FTLD-TDP, abnormally phosphorylated and ubiquitinated versions of TDP-43 manifest with different morphology and are grouped according to the number of neuronal cytoplasmic inclusions, dystrophic neurites, and glial cytoplasmic inclusions into subtypes A, B, C, and D ( 13 ). Approximately 90% of svPPAs present TDP-43 type C, FTD-MND is almost exclusively related to type B, amyotrophic lateral sclerosis (ALS) is related to types B and D, and bvFTD and nfvPPA are related to types A and B ( 6 , 14 ).

The FUS protein (fused in sarcoma) is one of several FET proteins (also including EWS and TAF15 proteins) associated with FTLD and ALS. FUS, like TDP-43, regulates mRNA and, in addition to being associated with bvFTD and PPA, is also a cause of ALS and neuronal intermediate filament inclusion disease ( 6 ). Functions linked to alternative splicing, transcription, and RNA transport are attributed to FUS. By affecting splicing, FUS dysfunction could affect normal MAPT expression, leading to an increased 4R-Tau–3R-Tau ratio ( 15 ).

FTD is strongly heritable. A positive family history is found in 30%−50% of cases, and in 10%−27%, the inheritance is autosomal dominant ( 2 , 16 – 18 ). In comparison, in less than 1% of AD cases, the inheritance is autosomal dominant ( 19 ). Additionally, genetic causes are found in 1%−10% of sporadic bvFTD cases ( 20 ). Thus, genetics is of fundamental importance in the assessment of patients with FTD ( 21 ). Numerous genes are associated with FTD; however, the most commonly implicated genes are MAPT , GRN , and C9orf72 .

MAPT , located on chromosome 17, is the gene encoding for the tau protein, whose function has been described previously. There are more than 50 known mutations for this gene. These mutations account for 5%−20% of familial FTD cases but are rarely found in sporadic forms of FTD (0%−2%) ( 21 ). Disease onset with these MAPT mutations varies but is often before 60 years of age. These mutations usually cause a bvFTD phenotype, but parkinsonism is often prominent.

Also located on chromosome 17 adjacent to MAPT is the GRN gene encoding for progranulin. This protein functions as a multifunctional growth factor in development, wound repair, neuroinflammation, autophagy, and lysosomal function ( 21 , 22 ). More than 70 known GRN mutations lead to the generation of nonsense mRNA, which is subsequently eliminated by physiological surveillance mechanisms, leading to haploinsufficiency of the progranulin protein, which thus leads to FTLD-TDP pathology by an unclear mechanism ( 23 , 24 ).

In 2011, it was described for the first time that the six-nucleotide noncoding repeat (G4C2) in the first intron of the C9orf72 gene, located on the short arm of chromosome 9, could lead to FTD, ALS, and FTD-MND ( 25 , 26 ). Up to 24 G4C2 repeats have been described in healthy control groups. Although there is no universally established cutoff point, it is suspected that more than 30 expansions increase susceptibility to neurodegeneration ( 26 , 27 ). Although the mechanism of pathogenicity by which this nucleotide expansion leads to the development of FTD is not well defined, multiple hypotheses have been formulated, including haploinsufficiency of the homonymous protein; toxicity from the transcribed, expanded-repeat-containing RNA; up- and downregulation of numerous proteins, including stathmin-2; and toxic dipeptide repeat (DPR) proteins ( 21 ). Regardless of the pathological mechanism by which it produces the disease, the C9orf72 mutation is the leading cause of familial FTD (20%−30% of cases) and the leading known genetic cause of sporadic FTD (6%) ( 21 , 28 – 30 ). In addition, this expansion leads to the accumulation of DPRs that aggregate in the cerebellum and hippocampus ( 31 ) and TDP-43 type A and type B pathology ( 14 ). Clinically, this mutation can present as bvFTD, ALS, or both and is characterized by a shorter disease duration (6.4±4.9 years) relative to other genes such as MAPT or GRN ( 32 ). However, a group of carriers of this mutation may have extremely slow-evolving forms of the disease syndromically indistinguishable from bvFTD, categorized as “FTD phenocopies” ( 33 ). Moreover, between 10% and 50% of patients with this mutation may manifest psychotic symptoms (hallucinations, delusions, or both), which may lead to confusing this disease with psychiatric conditions such as schizophrenia, bipolar disorder, or obsessive-compulsive disorder ( 2 , 27 , 34 ).

There are recommendations for genetic testing for the three main bvFTD-related genes ( MAPT , GRN , and C9orf72 ) in patients with at least one affected first-degree relative. This recommendation extends to FTD or early-onset dementia relatives, but a history of ALS, Parkinson’s disease, or unexplained late-onset psychiatric disorders should also be considered ( 2 ). Also, because of its association with sporadic cases of FTD, one should look for C9orf72 mutations in cases of late-onset behavioral symptoms (even if they do not meet all criteria for bvFTD), and there are no neuroimaging abnormalities, as a diagnostic element ( 2 ). With a significant proportion of apparent sporadic cases that are due to unexpected mutations, several groups are moving toward genetic testing in all FTD cases, even without family history. This approach will become more routine when therapies become available.

Commonly, when mental health professionals explain the diagnosis of FTD to patients and their family members, they are often concerned about the heritability of the disease. Before obtaining genetic testing, the implications for the individual and their family unit should be discussed with a genetic counselor. Family members may also be interested in genetic testing. Genetic counseling has a cost and can have legal and, sometimes, ethical implications. Before testing a family member (or members), the ideal scenario is to have the affected gene identified and search for the mutation in those concerned. This is not always possible, for various reasons. For example, affected relatives may be deceased; the afflicted patient may refuse to be tested, and so forth. When the test for a single gene is negative, another gene may be responsible for the clinical syndrome ( 35 ). Even when the presence of a mutated gene is demonstrated, it is not possible to predict the exact age of onset, severity or type of symptoms, or the course of the disease ( 35 ). Also, there are numerous factors to consider when evaluating whether to perform genetic testing. For example, does the person understand what having the mutation implies, or will the genetic result affect the person’s life decisions? Additionally, it is important to consider what psychological impact this information can have and whether the patient is prepared for this information ( 36 ). These decisions also have legal and economic consequences, including the possibility that the result affects the patient’s health insurance coverage or the possibility that this information can be used by an employer to decide whether to hire the person. In the United States, in 2008, the Genetic Information Nondiscrimination Act, or GINA, was passed at the national level to prohibit information such as this from being used in the context of administrative decisions such as health insurance or employment decisions ( 37 ). However, many countries do not have similar legislation on this type of information, which could potentially expose mutation carriers to stigma and marginalization.

THE DIAGNOSTIC PROBLEM IN FTD

The diagnosis of bvFTD is particularly challenging because of the absence of molecular biomarkers except for imaging and, therefore, depends principally on clinical assessment ( 2 ). In addition, the symptomatic overlap with primary psychiatric disorders (PPDs) including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders, and even personality disorders ( 38 ) means that PPDs often constitute the main differential diagnosis of bvFTD ( 39 ). Around 50% of patients with bvFTD have received a previous psychiatric diagnosis (most frequently, major depression), and the average diagnostic delay is up to 5–6 years from symptom onset ( 40 , 41 ).

BURDEN OF FTD

The years leading up to a patient’s bvFTD diagnosis are often the most stressful period in the lifetime of a spouse and other family members ( 42 ). Marital strife; financial chaos, or even ruin; and estrangement from friends and family are common and may create resentment toward the patient that persists even after a neurologic diagnosis has been made ( 42 ). Caregiver emotional responses to a bvFTD diagnosis are often mixed ( 42 ). The diagnosis creates enormous grief because of the prognosis: progression to death within 5–7 years ( 43 ). The socioeconomic burden of FTD is high. FTD is associated with substantial direct and indirect costs, diminished quality of life, and increased caregiver burden ( 44 ). The economic burden for FTD in the United States is approximately twice that reported for AD ( 44 ).

LEGAL ASPECTS

Brain disorders have long been considered as a cause of criminal behavior ( 45 ). This seems to be particularly true in the case of FTD, where such behaviors can be found in up to 50% of cases ( 46 , 47 ), up to five times more frequent than in patients with AD ( 48 ). One of the most prominent symptoms in FTD is behavioral disinhibition ( 3 ). These behaviors are often labeled as disinhibited because they break with social norms and frequently transgress legal boundaries ( 49 , 50 ). There are at least two forms of disinhibition ( 51 ): impulsivity, acts involving general rule violations that are related to an impairment of cognitive control mechanisms ( 49 ); and person-based disinhibition, where the behavior is more related to disturbed interpersonal interactions violating social tact and personal boundaries ( 52 ), in which case behaviors may emerge because of the compromise of cognitive systems related to semantic knowledge ( 53 ) or personal salience ( 54 ). This type of behavior has been labeled as “acquired sociopathy” ( 55 ). Because antisocial behavior in patients with FTD arises as a result of compromised functioning of brain structures responsible for directly or indirectly modulating behavior, these cases present a challenge in defining the degree of autonomy in their actions, this being particularly true for the early stages of the disease ( 56 ). Thus, this disease presents a challenge for the criminal justice system.

NEUROPSYCHIATRIC SYMPTOMS AND MANAGEMENT

FTD is a devastating, progressive neurodegenerative disease characterized by changes in personality, behavior, and language. In this sense, bvFTD is the variant that produces the most profound and limiting behavioral changes, compromising social functioning through symptoms such as behavioral disinhibition, apathy, and loss of empathy ( 3 ). In both forms of PPA, language impairment is the predominant feature, leading to significant limitations in social interactions and activities of daily living. Moreover, both svPPA and nfvPPA are not exempt from manifesting, throughout their evolution, behavioral symptoms that are similar to those observed in bvFTD that further compromise the functionality and quality of life of these patients and their caregivers ( 57 ). Additionally, there is evidence that symptoms such as apathy and disinhibition can manifest across the entire FTLD spectrum ( 58 ). This makes the management of neuropsychiatric symptoms a priority for clinicians. No disease-specific treatment interventions for FTD exist, there are only symptomatic treatments that are partially effective. Consequently, treatment largely remains supportive and involves a combination of nonpharmacological and pharmacological measures aimed at reducing the effect of distressing symptoms ( 59 ).

Nonpharmacological Interventions

Behavioral management..

Ikeda et al. ( 60 ) reported that troublesome behavioral symptoms were managed by reintroducing old hobbies and favorite games in six patients with FTD. They also reported that those methods were helpful for reducing social misconduct and disinhibition. They also reported that some patients who were treated with a behavioral therapy called “routinizing therapy”—in which stimulus-bound and stereotypic behaviors are replaced with appropriate behaviors—improved. This therapy was reported to help manage troublesome behaviors and contribute to a stable routine ( 61 ). The antecedent-behavior-consequence (ABC) model is a strategy often used in education for dementia caregivers, although there have been no studies of its effectiveness. The A, or antecedent, is the event or factors that initiate or contribute to the occurrence of the behavior. Antecedents are often called “triggers.” The B, or behavior, is the specific behavioral symptom. The C, or consequences, are all the reactions and responses of others after the behavior ( 62 ). In the case of compulsive activities, substitutions may have positive results. It consists of offering a squeeze ball to hold, instead of touching strangers, or offering a lollipop to diminish repetitive and compulsive vocalizations ( 63 , 64 ). Overall, behavioral management techniques that target disease-specific behaviors and preserved functions seem to be more effective than cognitive training in patients with FTD ( 65 ).

Environmental strategies.

As each patient faces different situations, it is difficult to conduct clinical studies of the environmental strategies. As such, most are mainly based on narrative and clinical experience, and no clinical studies that provide evidence on these environmental strategies exist ( 65 ). Environmental strategies are the least restrictive to the patient and focus on modifying the environment of the patient. Examples may include limiting access to credit cards, changing the family schedule to meet the preferences of the patient, or posting reminder notes and signs ( 62 ). It is recommended that patients keep the same daily routine and that objects or furniture are kept in the same position around them. In addition, to minimize disruptions, caregivers may change their schedule to accommodate a patient’s relatively harmless rituals, or a family may choose restaurants that the patient already knows ( 65 ). Reducing noise and stimulation, lessening clutter, turning off music, or simplifying social situations can help these patients to accurately focus on a designated task or response. Removing access to problematic items (e.g., credit cards, mail) or modifying public outings to reduce the opportunity for inappropriate interactions are examples of FTD-specific environmental manipulations ( 66 ). A supportive environment with normal lighting, moderate sound, a small number of people, and appropriate cueing were more likely to decrease behavioral symptoms in dementia ( 67 ). Exercise has been suggested to reduce behavioral symptoms ( 68 ), and aberrant motor behavior may respond to physical activity ( 69 ). Strategies for psychotic symptoms include environmental modifications such as removing mirrors or increasing lighting, which may reduce the propensity for misinterpretation ( 69 ).

Caregiver intervention.

Caregiver intervention should be the most effective treatment within the context of dementia ( 70 ). Behavioral changes rather than level of disability seem to be correlated with caregiver distress and burden in bvFTD ( 71 ). The ABC strategy has shown a reduction in behavioral symptoms and improved caregiver outcomes for behavior management ( 72 ). The key to reducing caregiver stress seems to lie in increasing their understanding of the symptoms and ways of dealing with challenging behaviors ( 70 ). Programs such as The Savvy Caregiver have shown similar results in promoting caregiver mastery regarding behavior management and reduced caregiver stress ( 73 – 75 ).

Speech therapy.

PPA is a debilitating disorder in which speech and language deteriorate as a result of neurodegenerative disease ( 76 ). Speech therapy is led by a language pathologist, who may offer a variety of interventions and compensatory strategies to patients with PPA ( 77 ). PPA interventions commonly tap strategies training individual word retrieval, trained scripts, and compensatory communication methods ( 78 ). A study by Henry et al. ( 76 ) included ten individuals with mild to moderate nonfluent-agrammatic variant PPA. They examined the immediate and long-term benefits of video-implemented script training for aphasia. They found that this treatment resulted in significant improvement in production of correct, intelligible scripted words for trained topics, a reduction in grammatical errors for trained topics, and an overall increase in intelligibility for trained as well as untrained topics at posttreatment. Follow-up testing revealed maintenance of gains for trained scripts up to 1 year posttreatment on the primary outcome measure. Performance on untrained scripts and standardized tests remained relatively stable during the follow-up period, indicating that treatment helped to stabilize speech and language despite disease progression ( 76 ).

Pharmacological Interventions

Pharmacological interventions should be implemented after a careful analysis of the case, ideally after nonpharmacological approaches have been exhausted, or the magnitude of the symptoms requires these interventions to be implemented promptly. In addition, possible reactions and adverse effects to these medications should be monitored, and the relevance of their indication should be re-evaluated periodically. Table 1 summarizes the pharmacological interventions along with the level of evidence and recommendation for them ( 79 ).

a For further details on the American Hospital Formulary Service Drug Information, see reference 79 . Level of evidence: 1=high strength or quality; 2=moderate strength or quality; 3=low strength or quality; 4=opinion/experience. Grade of recommendation: 1=recommended (accepted); 2=reasonable choice (accepted, with possible conditions); 3=not fully established (unclear risk or benefit, equivocal evidence, inadequate data or experience); 4=not recommended (unaccepted). L-DOPA=levodopa-3,4-dihydroxyphenylalanine.

TABLE 1. Level of evidence and strength of recommendation of frontotemporal dementia pharmacological treatments classified according to the American Hospital Formulary Service Drug Information a

Selective serotonin reuptake inhibitors (SSRIs).

FTD has been shown to have serotonergic network disruption on the basis of autopsy, neuroimaging, and CSF studies ( 80 , 81 ). Some studies suggest that SSRIs are effective in helping with various symptoms of FTD, including disinhibition, impulsivity, repetitive behaviors, and eating disorders ( 82 ), and they also suggest that the behavioral symptoms of FTD may improve after treatment with SSRIs ( 70 , 83 ).

One study concluded that long-term treatment with paroxetine may influence noncognitive aspects of FTD, with improvements in behavior and social conduct as evidenced by a reduction in aggressiveness, agitation, weeping and depressed mood, social conduct, eating problems, and sleep disorders ( 84 ). A small study with paroxetine at doses of 20 mg/day for 14 months showed improvement in scores on the Neuropsychiatric Inventory (NPI) and was well tolerated ( 85 ). However, another study conducted with paroxetine versus placebo with doses increasing up to 40 mg/day reported that there was no significant improvement and that, moreover, it could worsen the cognitive profile of patients ( 86 ). The discrepancies between these studies are attributed to a better response to and tolerability of paroxetine at lower doses (20 mg/day) ( 87 ); however, an alternative hypothesis is that the worse performance, especially in the cognitive domain, with higher doses (40 mg/day) is due to the anticholinergic effect of paroxetine ( 88 ).

A study by Herrmann et al. ( 89 ) reported that citalopram treatment was effective in treating behavioral symptoms, with significant decreases in NPI total score, disinhibition, irritability, and depression scores over 6 weeks. The significant improvement in Frontal Behavior Inventory scores suggested that citalopram was also effective in treating FTD-specific behaviors ( 89 ). A more recent randomized, double-blinded, placebo-controlled study of 12 patients with doses of citalopram at 30 mg/day showed improved disinhibition and related cognitive functions. This effect was attributed to the restoration of impaired serotonergic neurotransmission in bvFTD ( 90 ).

There is limited information on the use of sertraline in FTD; in one study, eight patients showed improvement in stereotyped movements and compulsive behavior with doses of sertraline between 50 and 100 mg over a period of 6 months ( 91 ). A case report of a 53-year-old patient with ALS-FTD and inappropriate sexual behavior reported symptomatic improvement with sertraline at doses of 100 mg/day ( 92 ).

A 12-week open-label study of 16 patients with FTD and behavioral symptoms with fluvoxamine at doses of 50–150 mg/day showed improvement in stereotypic behavior, eating behavior, and roaming behavior ( 93 ). One paper reported two cases of FTD with symptoms of stereotypic behavior and compulsive complaint of abdominal pain where the use of fluvoxamine improved both symptoms ( 94 ).

Trazodone has been effective in treating agitation and aggression in FTD and may also function as a sleep aid, if necessary ( 82 ). In one study, it was also found that trazodone can reduce the behavioral symptoms of FTD that were assessed by the NPI score, especially eating disorder, irritability, agitation, and depressive symptoms ( 95 ).

Second-generation antipsychotics.

Although off-label use of antipsychotics in FTD is common ( 88 ), there are a few studies that support the use of these drugs for the control of behavioral symptoms in this disease. Concern about the association between the use of antipsychotics in older adults and increased risk of stroke led the U.S. Food and Drug Administration (FDA) in 2005 to issue a boxed warning for the use of this medication in dementia-related psychosis. Despite this, guidelines for the management of behavioral symptoms in dementia, such as the American Psychiatric Association guideline ( 96 ) and the International Psychogeriatric Association guideline in 2018, recommend the use of second-generation antipsychotics for symptoms such as agitation and psychosis in dementia. Because of the limited number of studies performed, it is unclear whether it is possible to translate these indications to FTD.

There is evidence that there is a deficit in dopaminergic neurotransmission across the spectrum of FTLD ( 97 ). Mesolimbic and mesocortical dopaminergic pathway involvement may be related to the manifestation of behavioral and cognitive symptoms ( 97 ). However, dopaminergic involvement in the nigrostriatal pathway may be related to the high prevalence of extrapyramidal symptoms observed in the course of the disease, making these patients particularly sensitive to the use of antipsychotics ( 98 – 100 ). Thus, if these drugs are used for the control of behavioral symptoms, antipsychotics with a lower D2 blockade profile (i.e., those with a lower incidence of associated extrapyramidal symptoms) are of choice. Among these drugs, quetiapine could be of particular relevance ( 101 , 102 ). Quetiapine was observed in a case series to demonstrate improvements in agitation in three patients with FTD ( 103 ), but no difference in NPI scores was shown between baseline and quetiapine treatment in a separate double-blind, crossover study with dextroamphetamine and quetiapine involving eight patients with FTD showing behavioral symptoms ( 104 ).

Under the same logic, clozapine is an antipsychotic that could potentially be useful in FTD. Unfortunately, to date, there are no studies on its use in this population. However, a case report of a patient with a diagnosis of FTD, refractory psychosis, and frequent episodes of aggression describes significant clinical improvement after starting clozapine up to a dose of 400 mg/day. Aripiprazole, because of its effect as a partial D2 agonist, could also be presented as a drug with less adverse effects in FTD. However, there are currently only case reports of its clinical use. One report describes symptomatic improvement in a patient with frequent sexual remarks ( 105 ). Similarly, a case of FTD with sexual disinhibition reports symptomatic improvement within 2 weeks with aripiprazole at 18 mg/day ( 106 ). A study with 17 patients related the use of olanzapine to a substantial improvement in symptoms such as delirium, affective lability, wandering, and irritability ( 85 ). However, the use of olanzapine, because of its greater D2 blockade, may increase extrapyramidal symptoms, and it is associated with significant metabolic syndrome and higher mortality than quetiapine ( 88 ). The use of antipsychotics with greater dopaminergic blockade, such as risperidone or first-generation antipsychotics, is not recommended because of the high incidence of motor adverse effects and higher mortality in dementia ( 88 ).

Anticonvulsants.

The use of anticonvulsants as mood stabilizers is common in the treatment of various psychiatric disorders, with bipolar disorder being one of its main indications in psychiatry. However, the use of anticonvulsants in treating patients with FTD is limited. Although there are several case reports where clinical utility is attributed to them, studies demonstrating this are lacking. Three case reports describe improvement in cases of FTD associated with hyperorality with topiramate, two of them in patients with binge eating ( 107 , 108 ) and alcohol misuse ( 109 ). One case report recounts improvement in symptoms of hypersexuality with carbamazepine ( 110 ). Similarly, some case reports related the use of valproate to improvement of symptoms such as hypersexuality and agitation ( 103 , 111 ). However, there is still little evidence to support anticonvulsants as a therapy in FTD.

Carbonate lithium.

As with many anticonvulsants, the use of lithium carbonate as a mood stabilizer in the treatment of patients with bipolar disorder is widespread. However, the evidence for its use in treating patients with FTD is extremely limited. A case series published by Devanand et al. ( 112 ) describes three cases of patients diagnosed as having FTD, previously treated with a combination of antidepressants and antipsychotics, with symptoms such as hallucinations and agitation where the use of low doses of lithium (300–600 mg/day) led to clinical improvement. One of these cases reported lithemia values of 0.4 mmol/L for a dose of 450 mg/day of lithium, whereas another case of the same series recorded lithemia values of 0.8 mmol/L for a dose of 300 mg/day of lithium; similarly, another case recorded symptomatic improvement in agitation with a dose of 600 mg/day but developed tremor and sedation when increasing the dose to 1,200 mg/day. On the other hand, a case reported by Arciniegas ( 113 ) of FTD misdiagnosed as late-onset bipolar disorder reported marked impairment in cognitive, behavioral, and motor functions after reaching lithium levels considered therapeutic; these symptoms improved when lithium was discontinued. A phase 2 study is currently active with low doses of lithium versus placebo for the treatment of behavioral symptoms in patients with FTD ( ClinicalTrials.gov identifier: NCT02862210). However, because of the current limited clinical evidence, the narrow margin of therapeutic safety and the risk of developing lithium toxicity, the use of this molecule should be considered with extreme caution by closely monitoring plasma lithium levels and closely evaluating cognitive, behavioral, or motor changes.

Stimulants.

There is evidence that shows a deficit in dopaminergic transmission in FTD ( 97 ). Dopaminergic dysfunction has been related to the presence of extrapyramidal symptoms but also some behavioral symptoms such as agitation, disinhibition, and apathy ( 114 – 116 ). A small double-blind, placebo-controlled study in patients with bvFTD found that the use of methylphenidate, a dopamine and noradrenaline reuptake inhibitor, at doses of 40 mg was able to improve decision-making behavior of patients ( 117 ). A case report of a 72-year-old patient with FTD and symptoms of apathy, behavioral disinhibition, and irritability treated with 18-mg methylphenidate and 100-mg bupropion showed marked and sustained symptomatic improvement ( 118 ). A study in eight patients with FTD treated with dextroamphetamine versus quetiapine showed that the stimulant was effective in decreasing apathy and disinhibition on the NPI subscales ( 104 ). A limitation of these studies is that they were performed with small samples, so it is difficult to generalize these results. Moreover, the use of psychostimulants carries possible adverse effects that should be considered and monitored in case of their use.

In a study by Jesso et al. ( 119 ), the effects of a single dose of intranasal oxytocin on neuropsychiatric behaviors and emotion processing were evaluated in patients with bvFTD. They designed a randomized, double-blind, placebo-controlled crossover design that included 20 patients with this diagnosis who received a 24-IU dose of intranasal oxytocin or placebo and then completed the emotion recognition tasks. Caregivers completed validated behavior ratings at 8 hours and 1 week after drug administration. There was a significant improvement in NPI scores on the night of oxytocin administration compared with placebo and baseline scores. Oxytocin was also associated with reduced recognition of angry facial expressions by patients with bvFTD. Jesso et al. ( 119 ) concluded that oxytocin is a potentially promising new symptomatic treatment candidate for patients with bvFTD and that further studies were needed. A phase 2 double-blind, randomized, multicenter study is currently active to test the safety, tolerability, and effects of intranasal syntocinon (synthetic oxytocin) versus placebo on behavioral symptoms of FTD ( 120 ).

Pharmacological treatment of motor symptoms.

As described in the section on antipsychotics, it is common for FTD patients to manifest extrapyramidal symptoms during the course of the disease. Up to 70% of patients present symptoms of rigidity, gait dysfunction, or bradykinesia in their evolution ( 98 – 100 , 121 ). The evidence on the use of pharmacological treatment for motor symptoms in FTLD focuses on PSP and CBD. In these cases, the use of L-dopa provides mild and transient improvement ( 122 , 123 ). The use of dopaminergic agonists in FTD is often discouraged because of their incidence of dopaminergic dysregulation syndrome, which may worsen behavioral symptoms ( 88 , 124 ). Within the monoamine oxidase inhibitors, there are data on three case reports that describe improvement in behavioral symptoms ( 125 ).

Memantine is, together with cholinesterase inhibitors, one of the molecules approved by the FDA for the specific treatment of AD. It is postulated that its mechanism of action as a noncompetitive inhibitor of N -methyl- d -aspartate (NMDA) receptors could decrease glutamate-mediated cytotoxicity and thus slow the progression of the disease. Although the neuropathological changes in FTD are different from those in AD, it was believed that its protective effect on neuronal injury could be beneficial in FTD. Likewise, evidence that memantine could improve behavioral symptoms in AD made this molecule a target to explore in FTD. However, two separate double-blind, placebo-controlled studies found that there was no significant improvement between the placebo and memantine groups and that it may even worsen cognition ( 126 , 127 ).

Cholinesterase inhibitors.

Unlike AD, in FTLD, the cholinergic system is relatively preserved ( 97 ). Despite this, approximately 40% of FTD patients receive treatment with cholinesterase inhibitors ( 128 ). Numerous studies have attempted to study the therapeutic efficacy of cholinesterase inhibitors in FTD. Not only have these studies failed to demonstrate a benefit from the use of these drugs, but, on the contrary, there is also evidence that they may actually worsen cognitive and behavioral performance ( 59 , 82 , 87 , 129 ).

CURRENT CLINICAL TRIALS AND BIOMARKERS

Molecule-based therapies are being considered for the genetic forms of FTD and to treat the symptoms of the disease ( Table 2 ). For each of the major genetic subtypes, MAPT , GRN , and C9orf72 , different approaches will be needed. Several advances have made it possible to consider such efforts. First, the discovery of powerful biomarkers such as the neurofilament light-chain protein (NfL) will make it possible to follow progression in a clinical trial, because NfL begins to rise during the transition from asymptomatic to mildly symptomatic FTD ( 130 ). Similarly, structural imaging can detect significant changes in atrophy over 6 months, making it likely that the magnetic resonance imaging (MRI) can also be used as a surrogate marker ( 131 ).

a ALS=amyotrophic lateral sclerosis; bvFTD=behavioral variant FTD; CBD=corticobasal degeneration; FTD=frontotemporal dementia; lvPPA=logopenic variant primary progressive aphasia; nfvPPA=nonfluent variant primary progressive aphasia; PKR=protein kinase R; PSP=progressive supranuclear palsy.

TABLE 2. Active clinical trials in frontotemporal lobar degeneration (FTLD) a

For MAPT carriers, the major emphasis of clinical trials will be to lower tau either by decreasing its production or by increasing its clearance. There is extensive evidence that lowering tau will ameliorate symptoms in animal models of AD and FTD ( 132 , 133 ). Further, in humans, antibodies against tau have been demonstrated to reach the brain and bring tau into the plasma ( 134 ), but clinical trials using antibodies for both AD and FTD have been disappointing. These failures have probably occurred because of relatively low levels of the antibody that cross the blood-brain barrier. Therefore, technologies such as antisense oligonucleotides and CRISPR could lower tau in a highly effective manner. If MAPT carriers treated with effective tau-lowering therapies show slowing or progression or even halting of the disease, these approaches will next be used to treat other tau-related forms of FTD. Other efforts are focused on increasing the degradation of tau in the lysosome or the proteosome ( 135 ).

With GRN , different mechanisms and different approaches are being considered. GRN mutation carriers show markedly reduced brain and blood levels of progranulin, suggesting a haploinsufficiency mechanism with the deficiency of progranulin production on one chromosome sufficient to cause FTD. Many strategies are being considered to increase brain progranulin, with many focused on better ways to deliver progranulin into the brain. Arrant and colleagues found, when using an AAV vector (AAV- Grn ) to deliver progranulin in Grn −/− mice, that lysosomal dysfunction and microglial pathology were both ameliorated ( 136 ). It is likely that, in the coming year, AAV transplantation studies will begin with GRN gene carriers, and others delivery systems are also being considered.

Finally, C9orf72 mutations produce a long hexanucleotide repeat that is already the target for gene carriers with ALS, and therapies for FTD are being considered. As with all these gene-related therapies, multiple questions will need to be answered regarding delivery of the drug to the brain; timing of the therapy (presymptomatic versus symptomatic); the reliability of biomarkers; and, most importantly, efficacy. A new chapter in therapy for FTD and related conditions is beginning. Once the genetic forms of the disease have been effectively treated, new approaches to the sporadic form of the disease are likely to emerge.

CONCLUSIONS

FTD is frequently misdiagnosed, and when the diagnosis occurs, it often comes late in the course of the illness or is missed. Recognition that behavioral changes represent a neurodegenerative condition is difficult, leading clinicians to diagnose a primary psychiatric disorder. Also, diagnostic tools such as blood biomarkers or neuroimaging can be difficult to access, particularly in low- and middle-income communities. Another barrier to its identification is the lack of knowledge and training for health care providers about FTD.

FTD treatment has been limited to the management of neuropsychiatric symptoms, these being the most prominent feature of the disease. Therapeutic strategies have focused on nonpharmacological interventions such as behavioral and environmental manipulation, caregiver interventions, and speech therapy for the language variants of FTD. Also, pharmacological treatment has also been used to treat these symptoms, with variable but sometimes positive results. With the advance of knowledge regarding the pathophysiology of FTD, pharmacological interventions such as the use of SSRIs, trazodone, or second-generation antipsychotics have a solid scientific basis for the treatment of FTD.

In the past 10 years, thanks to new techniques in neuroimaging, genetics, and biomarker analysis, much has been discovered about the phenomena underlying frontotemporal lobar degeneration. This has allowed the design of new molecule-based therapies that are still in the early stages of research but show promising results.

This work was supported by the National Institute on Aging: grant P01-AG019724 to the Frontotemporal Dementia Program of the University of California, San Francisco and grant P30-AG062422 to the Alzheimer’s Disease Research Center.

The authors report no financial relationships with commercial interests.

Dr. Magrath Guimet and Dr. Zapata-Restrepo contributed equally to this study.

The authors thank the Global Brain Health Institute, the Memory and Aging Center, and the Alzheimer Disease Research Center, University of California, San Francisco.

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Decoding Dementia: How a Brain Protein Could Lead to New Treatments

By Indiana University School of Medicine December 28, 2023

Researchers discovered a crucial protein, TAF15, in frontotemporal dementia (FTD) cases. This finding, offering new treatment avenues, was achieved using advanced neuropathologic and molecular techniques, marking a breakthrough in understanding and potentially treating this form of dementia.

Discovery could lead to new, targeted therapeutics for frontotemporal dementia.

An international team of researchers including experts at the Indiana University School of Medicine has identified a protein found in the brains of people with frontotemporal dementia (FTD), discovering a new target for potential treatments for the disease.

Understanding Frontotemporal Dementia

According to the National Institutes of Health , FTD results from damage to neurons in the frontal and temporal lobes of the brain. People with this type of dementia typically present symptoms, including unusual behaviors, emotional problems, trouble communicating, difficulty with work, or in some cases difficulty with walking, between the ages of 25 and 65.

Research Breakthrough in Neurodegenerative Disorders

Neurodegenerative disorders, including dementias and Amyotrophic Lateral Sclerosis (ALS), occur when specific proteins form amyloid filaments in the nerve cells of the brain and spinal cord. The multidisciplinary team of researchers—including members from the Medical Research Council (MRC) Laboratory of Molecular Biology, the IU School of Medicine and the University College London Queen Square Institute of Neurology—found that in cases of FTD, a protein called TAF15 forms these amyloid filaments in the cells of the brain and the spinal cord. On December 6, they published their findings in the journal Nature .

Cryo-EM structure of TAF15 amyloid filaments as discovered in patients with frontotemporal dementia. Credit: Indiana University

Bernardino Ghetti, MD is a Distinguished Professor at the IU School of Medicine and has been studying neurodegenerative dementias for 50 years. As a lead neuropathologist on the project, Ghetti and his team studied the protein aggregates from brains donated by four people who had frontotemporal dementia and motor weakness. Together with their colleagues in the UK, IU researchers used neuropathologic and molecular techniques and cutting-edge cryo-electron microscopy (cryo-EM) at atomic resolution to discover the presence of the amyloid filaments made of TAF15 protein in multiple brain areas. However, it is important to note that TAF15 amyloid affects also nerve cells of the motor system.

Important Breakthrough

“This discovery represents an important breakthrough that recognizes TAF15 as a potential target for the development of diagnostic and therapeutic strategies toward a lesser-known form of frontotemporal lobar degeneration associated with frontotemporal dementia,” Ghetti said.

Reference: “TAF15 amyloid filaments in frontotemporal lobar degeneration” by Stephan Tetter, Diana Arseni, Alexey G. Murzin, Yazead Buhidma, Sew Y. Peak-Chew, Holly J. Garringer, Kathy L. Newell, Ruben Vidal, Liana G. Apostolova, Tammaryn Lashley, Bernardino Ghetti and Benjamin Ryskeldi-Falcon, 6 December 2023, Nature . DOI: 10.1038/s41586-023-06801-2

Additional authors on the study are the MRC Laboratory of Molecular Biology’s Stephan Tetter, Diana Arseni, Alexey G. Murzin, Sew Y. Peak-Chew and Benjamin Ryskeldi-Falcon; the University College London’s Yazead Buhidma and Tammaryn Lashley; and the IU School of Medicine’s Holly J. Garringer, Kathy L. Newell, Ruben Vidal and Liana G. Apostolova.

The study was in part funded by the NIH’s National Institute on Aging and National Institute of Neurological Disorders and Stroke.

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• Open access
• Published: 20 December 2023

Statins and cognitive decline in patients with Alzheimer’s and mixed dementia: a longitudinal registry-based cohort study

• Bojana Petek 1 , 2 , 3 ,
• Henrike Häbel 4 ,
• Hong Xu 5 ,
• Marta Villa-Lopez 5 , 6 , 7 ,
• Irena Kalar 1 , 3 , 8 ,
• Minh Tuan Hoang 5 , 9 ,
• Silvia Maioli 1 , 10 ,
• Joana B. Pereira 11 ,
• Shayan Mostafaei 5 , 9 ,
• Bengt Winblad 1 , 12 ,
• Milica Gregoric Kramberger 1 , 3 , 8 ,
• Maria Eriksdotter 5 , 12 &
• Sara Garcia-Ptacek 5 , 12  

Alzheimer's Research & Therapy volume  15 , Article number:  220 ( 2023 ) Cite this article

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Disturbances in brain cholesterol homeostasis may be involved in the pathogenesis of Alzheimer’s disease (AD). Lipid-lowering medications could interfere with neurodegenerative processes in AD through cholesterol metabolism or other mechanisms.

To explore the association between the use of lipid-lowering medications and cognitive decline over time in a cohort of patients with AD or mixed dementia with indication for lipid-lowering treatment.

A longitudinal cohort study using the Swedish Registry for Cognitive/Dementia Disorders, linked with other Swedish national registries. Cognitive trajectories evaluated with mini-mental state examination (MMSE) were compared between statin users and non-users, individual statin users, groups of statins and non-statin lipid-lowering medications using mixed-effect regression models with inverse probability of drop out weighting. A dose-response analysis included statin users compared to non-users.

Our cohort consisted of 15,586 patients with mean age of 79.5 years at diagnosis and a majority of women (59.2 %). A dose-response effect was demonstrated: taking one defined daily dose of statins on average was associated with 0.63 more MMSE points after 3 years compared to no use of statins (95% CI: 0.33;0.94). Simvastatin users showed 1.01 more MMSE points (95% CI: 0.06;1.97) after 3 years compared to atorvastatin users. Younger (< 79.5 years at index date) simvastatin users had 0.80 more MMSE points compared to younger atorvastatin users (95% CI: 0.05;1.55) after 3 years. Simvastatin users had 1.03 more MMSE points (95% CI: 0.26;1.80) compared to rosuvastatin users after 3 years. No differences regarding statin lipophilicity were observed. The results of sensitivity analysis restricted to incident users were not consistent.

Conclusions

Some patients with AD or mixed dementia with indication for lipid-lowering medication may benefit cognitively from statin treatment; however, further research is needed to clarify the findings of sensitivity analyses.

The brain houses about a quarter of the cholesterol present in the body, making it the richest cholesterol-containing organ [ 1 ]. The essential role of brain cholesterol is reflected in its involvement in numerous physiological processes such as maintaining membrane integrity, neurotransmission and synaptogenesis [ 2 ]. A dysregulation of brain cholesterol homeostasis may be involved in the pathogenesis of Alzheimer’s disease [ 2 ] through interference with the amyloidogenic Aβ pathway [ 3 ], impairment of cerebral blood flow [ 4 ], and other mechanisms [ 5 ]. On the other hand, the association of peripheral hypercholesterolemia and cognition is complex. Peripheral hypercholesterolemia in midlife has been linked to cognitive decline and AD in late-life [ 6 , 7 ] through different mechanisms [ 7 , 8 , 9 , 10 ]. Moreover, genetic polymorphism of brain cholesterol transporter ApoE4 and several additional genetic factors implicated in lipid metabolism could be relevant to AD pathogenesis [ 11 , 12 ]. In contrast, peripheral hyperlipidaemia in late life is a marker of a better general health and cognition [ 13 , 14 ].

The possible cognitive effects of HMG-CoA reductase inhibitors or statins, which are used in cardiovascular disease prevention, have sparked extensive research in the last few decades. Based on their pharmacokinetic characteristics, statins can be divided according to their structure (fungus-derived or synthetical), lipophilicity, metabolism, bioavailability, potency and binding to different proteins and transporters [ 15 ]. The multi-layered effects of statins on cognition are translated through numerous neurodegenerative processes in a cholesterol-dependent as well as independent (´´pleiotropic´´) manner [ 15 , 16 ]. Statins seem to interfere with the amyloidogenic cascade [ 17 ] and phosphorylation of tau [ 18 ], provide beneficial vascular factors through endothelial function and clearance of neurotoxic substances [ 19 ], decrease neuroinflammation and oxidative stress as well as promote neuronal survival and plasticity, synaptogenesis and neurotransmission [ 16 ].

The overall cognitive effects of statins are likely connected to a complex interaction of factors, related to the patient’s characteristics, integrity of blood–brain barrier permeability [ 20 ], characteristics of statins [ 18 ], time of treatment, dosages as well as critical time windows in the pathogenesis of dementia [ 21 , 22 ] (Fig. 1 ).

Interaction between the patient’s and medication’s characteristics potentially influence the cognitive effects of statins. Two separate cholesterol pools in the body are thought to be connected to the risk of Alzheimer’s disease (AD), central and peripheral. The brain penetration of statins has been attributed to different factors linked to BBB crossing (lipophilicity of a statin, chemical structure, molecular weight and size of the molecule, different transporters and their genetic polymorphisms). The structure of the barrier itself additionally influences the permeability of statins and is affected by aging, neurodegenerative processes and possibly, peripheral hypercholesterolemia. The overall cognitive effects of statins are likely a result of their central and peripheral actions and are connected to the time of intervention in life and the pathogenesis of AD. Moreover, an interaction of comorbidities and comedication, a sufficient time of treatment and dosages are important. In midlife, protective effect of statins against AD could be achieved through lowering the metabolic risk of hyperlipidaemia. BBB blood–brain barrier, AD Alzheimer’s disease

Despite the extensive number of observational cohort studies and some clinical trials on statins, their ability to prevent dementia or ameliorate cognitive decline after disease onset is still unclear. A number of mild and reversible short-term cognitive adverse effects [ 23 , 24 ] contributed to a warning for the labelling of statins by the US Food and Drug Administration. However, numerous large systematic reviews and meta-analyses have not confirmed these adverse cognitive effects [ 25 , 26 , 27 , 28 , 29 ] and some suggested that the use of statins may lower the risk of AD [ 25 , 30 , 31 , 32 , 33 ]. Clinical trials generally reported a null effect [ 34 , 35 , 36 ] but were commonly underpowered or used less robust cognitive evaluation tools. Comparably less information is available regarding the effect of statins on cognitive decline in patients with established AD [ 37 , 38 , 39 , 40 ]. Epidemiological biases inherent to observational design or a heterogeneous design of studies partly explain these discrepancies [ 41 ].

The aim of our study was to evaluate the association between statin use and cognitive decline over time in a large cohort of patients diagnosed with AD or mixed AD dementia. We hypothesized that statins that cross the BBB would be associated with less cognitive decline evaluated with mini-mental state examination (MMSE) in these patients.

Study design and registries

We performed a longitudinal cohort study of patients with AD or mixed dementia and indication for lipid-lowering treatment, registered in the Swedish registry for dementia (SveDem). SveDem is a nationwide quality-of-care registry, established in 2007 [ 42 ]. All memory clinics and 78 % of primary care centres in Sweden report to SveDem [ 43 ]. From this registry, we obtained demographic information (age, sex, living arrangements), date and care unit of registration, type of dementia diagnosis and cognitive status of the patients (MMSE scores) at baseline and follow-ups. The date of the dementia diagnosis in SveDem was set as the index date; 61% of patients had only one entry, 26% had two, 8% had 3 and 5% had more than 3. In total, 80,004 individual patients with dementia were registered in SveDem between 2007 and 2018. All patients were followed until death, emigration or end of follow-up (16 October 2018).

All patients with a missing MMSE score at index date were excluded from the analyses. Only patients diagnosed with hyperlipidaemia (ICD-10 codes from E78.0 to E78.6 obtained from the the Swedish National Patient Registry (NPR), see below) in the preceding 10 years before the index date or those with a prescription of statins (ICD-10 code C10 obtained from the Swedish Prescribed Drug Registry (PDR), see below) in the preceding 6 months before the index date were included in the analyses. Furthermore, the top 1% of statins users sorted by averaged defined daily doses (DDD) were excluded as well, assuming that their consumption data was falsely high and that these individuals bought medication that they did not consume. Figure 2 shows the patient selection flowchart: 15,586 individuals were included for the main analysis.

Flowchart of study participants selection. Hyperlipid patients with AD or mixed dementia, registered in SveDem from 2007 to 2018 were included in the study. Among these, we compared cognitive trajectories over time, evaluated with MMSE, in different comparison groups: (1) statin users vs non-users of statins, (2) simvastatin users vs atorvastatin users, (3) simvastatin users vs rosuvastatin users, (4) lipophilic statin users vs hydrophilic statin users, (5) fungal statin users vs synthetic statin users and (6) non-statin lipid-lowering medications users vs statin users

The exposure drug use was extracted for every SveDem entry. Drug use was defined from the PDR as either the average DDD during the 6-month period preceding each SveDem entry date or simply as a categorical variable (yes/no) during the same period (time-updated exposure). Time-updated exposure means that presence/absence and dose of statins was examined in each 6-month period leading up to each measurement of MMSE (baseline or follow-up). Individual patients starting their statin treatment after the index date were excluded from the analyses because cognitive decline could have affected prescription. All other patients were included in the analyses as non-users. DDD is defined by the World Health Organization as the assumed average maintenance daily dose of a medication for its primary indication in adults [ 44 ]. One DDD of simvastatin is equivalent to 30 mg of simvastatin or 20 mg of atorvastatin.

Medication use

Medication use with their corresponding ATC codes were collected from the PDR that was established in 2005, which includes all prescription medication dispensed at Swedish pharmacies [ 45 ]. Lipid-lowering medications included simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin, fibrates, bile acid sequestrants, nicotinic acid and derivates and other non-statin lipid lowering medications. Comedications were calculated as time-updated exposures (yes/no) during the 6-month period preceding the index date. Comedications were selected based on known relevance for patients with dementia and included cardiac drugs, vasoprotectives, platelet aggregation inhibitors, anticoagulants, antipsychotics, anxiolytics, hypnotics, antidepressants, cholinesterase inhibitors, memantine and vitamin D ( Appendix ). Assumption on the adherence was made based on the collection of the medication at the pharmacy.

Comorbidities

Comorbidities were obtained with their corresponding ICD-10 codes from the NPR and were coded dichotomously up to 10 years before index date. NPR covers all diagnoses from in-hospital and specialist clinics. Comorbidities were selected based on their known relevance for cognition in patients with dementia and included diabetes mellitus, arrythmia, heart failure, atrial fibrillation, alcohol-related disease, chronic kidney disease, cardiovascular disease, ischemic heart disease, respiratory disease, stroke, anaemia, liver disease, malignancy and obesity ( Appendix ).

Covariates that were considered included age at baseline, sex (male/female), residency (living with another adult/alone/nursing home/missing), type of dementia diagnostic unit (special memory clinic/primary care centre) and calendar year of dementia diagnosis, all at index date. We selected the covariates that are likely associated with cognitive functions or the probability of receiving statins, based on previous research and/or our clinical knowledge.

The linkage of data from the forementioned registries—SveDem, Swedish National Patient Registry, and Swedish Prescribed Drug Registry—was allowed by the personal identification number of each Swedish citizen. Patient identification was pseudonymized and blinded to the researchers.

The main outcome was cognitive decline, evaluated with MMSE points.

Statistical analysis

The data were described in terms of mean and standard deviation (SD) for continuous variables and as positive counts (percentages) for categorical variables.

Linear mixed-effects regression models with random intercept and slope were used to investigate the change in MMSE scores over time and to detect differences between statin users and non-users. The model included statin use and time from index date as continuous variables and an interaction between drug use and time. Following our previous work in SveDem [ 46 ], a linear trend over time was assumed and the model allowed for a random intercept and random slope for each patient. This model is referred to as the crude model. In an adjusted model, comedications, comorbidities and other covariates were included in the model mostly as categorical variables. Only age, MMSE scores and calendar year at index date were treated as continuous variables. Fully adjusted models included clinical and demographic characteristics (MMSE score at baseline and age at diagnosis, year of diagnosis, sex, residency, comorbidities and comedications). Inverse probability weighting was used to account for the potential effects of general attrition from those lost to follow-up due to dropout. For this purpose, a logistic regression model was fitted to the data to estimate the probability of dropping out within the subsequent year. Dropout was defined as the last observed MMSE score without death or study end occurring in the subsequent year. For more details, see Handels et al. [ 47 ].

The analyses were repeated for selected drug groups where drug use was defined as yes/no during the 6-month period before each SveDem entry date and in subgroups defined by gender and age. We split the cohort at the mean age at index date (79.5 years) to create subgroups of younger and older patients. We compared individual statin users. We considered two approaches to divide the statins regarding their functional properties: firstly, lipophilic (simvastatin, atorvastatin, fluvastatin, lovastatin and pitavastatin) or hydrophilic groups (rosuvastatin, pravastatin) [ 48 ]. Moreover, we classified them into fungus-derived (simvastatin, pravastatin, lovastatin) or synthetic statins (atorvastatin, cerivastatin, fluvastatin, rosuvastatin, pitavastatin) [ 15 ]. Finally, we compared statin users to non-statin lipid-lowering medication users. To evaluate the association between the comparison groups after 3 years, we calculated a theoretical linear extrapolation based on the mixed effect models.

Multiple imputations of MMSE scores [ 47 ] and incident users models were two additional models we performed as a sensitivity analysis to check the robustness of our results. The first model deals with bias arising from missing MMSE scores at follow-ups and the second addresses the length of treatment as confounding. Incident users were defined as drug users who did not take out any drug prescription of statins during 12 months before 6-month period preceding each SveDem entry date. Table 1 shows the design of the study.

The cluster robust sandwich estimator was used to estimate standard error of the estimations and two-sided p -values were reported. All analyses were conducted using STATA version 16.1 (StataCorp, College Station, TX).

Characteristics of study population

As shown in Table 2 , our cohort consisted of 15,586 AD or mixed dementia patients with a mean age of 79.5 years (SD = 6.8) at dementia diagnosis. Most patients were women (59.2%). At baseline, all patients scored on average 21 points on MMSE (SD = 5); 10,869 patients (69.7%) used statins in the observation period. The most prescribed statin in the whole cohort was simvastatin (8235, 52.8%) followed by atorvastatin (2210, 14.2%). There were 296 (1.9%) users of a non-statin lipid-lowering medication. Most of the patients resided at home (53.9% with another adult and 40.7% alone) and 5% lived nursing homes. The most common comorbidities in the cohort were hypertension (40.1%), diabetes mellitus (24.4%) and cardiovascular disease (24%).

The average time of follow-up was 0.86 (SD = 1.40) years and average number of MMSE follow-ups for a patient with measures of MMSE was 1.61 (SD = 0.97). The average decline per year of the cohort was −1.20 points MMSE (95% CI: −1.32; −1.09). The average cognitive decline observed among 6113 patients with at least two MMSE measurements was −2.61 points (SD = 4.57).

Statin users were more commonly male (44 % vs 33.5 %, p < 0.001), younger (78.7 vs 80.7 years at baseline, p < 0.001) and had a better cognitive status at baseline (21.3 vs 20.8 MMSE points, p < 0.001), compared to non-users of statins. As expected, there was a higher prevalence of comorbidities in the former compared to the latter group, such as hypertension, cardiovascular disease, liver disease and diabetes mellitus. Statin users were more likely to be prescribed co-medication, such as antithrombotics, antihypertensives, antidiabetics or psycholeptics. More detailed information is presented in Tables 2 and 3 .

The sensitivity analysis revealed that a majority of our cohort had used statins at some point in time. Overall, 844 patients were incident users of statins. Compared to incident simvastatin users ( n = 557), incident atorvastatin users ( n = 267) had a lower baseline MMSE (20.5 vs 21.4 points, p = 0.01) and less commonly received their dementia diagnosis at special memory clinic (60.3 % vs 78.8 %, p < 0.001). (Supplementary table 7 ).

Cognitive decline in different treatment groups

Statin users compared to non- users of statins.

Statin use was associated with a slower cognitive decline over time compared to no use of statins. After taking an average of 1 DDD of statins for a year, statin users had 0.21 more MMSE points (95% CI: 0.12; 0.32) compared to non-users. There was a dose-response effect. After 3 years of taking an average 1 DDD of statins, statin-treated patients had 0.63 points more MMSE points (95% CI: 0.33; 0.94) (Table 4 , Fig. 3 ). These results were consistent in subgroup analysis and when considering imputed missing MMSE values and analysis restricted to incident users (Supplementary table 6 ) and in subgroup analyses (Supplementary table 1 ). We conducted post hoc analyses stratifying by dementia type (Alzheimer or mixed dementia; results not shown) with similar results to those presented for the whole group.

Cognitive decline, evaluated with change in MMSE score over time, in statin users compared to non-users of statins. The graph shows the association between increasing doses of statin treatment and MMSE over time, as predicted from the model. Linear mixed-effects regression model, adjusted for demographic characteristics, comorbidities and comedication, with inverse probability weighting. DDD defined daily dose. DDD is defined by the World Health Organization as the assumed average maintenance daily dose of a medication for its primary indication in adults. Yearly visit 1 represent the first MMSE measurement (baseline)

Simvastatin users compared to atorvastatin users

Simvastatin users exhibited a slower cognitive decline over time, compared to atorvastatin users (0.35 more MMSE points per year of follow-up, 95% CI: 0.03; 0.67 and 1.01 more MMSE points after 3 years, 95% CI: 0.06; 1.97) (Table 4 , Fig. 4 ).

Cognitive decline, evaluated with change in MMSE score over time, in simvastatin compared to atorvastatin users. Linear mixed-effects regression model, adjusted for demographic characteristics, comorbidities and comedication, with inverse probability weighting. Yearly visit 1 represent the first MMSE measurement (baseline)

When stratifying analyses for gender and age, the protective association for cognition of simvastatin compared to atorvastatin, was only statistically significant in the participants aged <79.5 years (which was the mean age of the total sample). Younger users of simvastatin had a slower decline of MMSE (0.28 points more per year, 95% CI: 0.03; 0.54, and 0.80 points more after 3 years, 95% CI: 0.05; 1.55) compared to younger atorvastatin users (Table 5 ).

This protective association was statistically significant in multiple imputations of MMSE model but not in incident users (0.56 less MMSE points per year, 95% CI: -1.13; 0.01) (Supplementary table 6 ). We conducted post hoc analyses stratifying by dementia type (Alzheimer or mixed dementia): in mixed dementia, simvastatin use was associated with 1.57 more MMSE points MMSE at 3 years (95% CI 0.79; 2.34) while results were not significant for the Alzheimer group (0.49 more points MMSE at 3 years; 95% CI -0.76; 1.76).

Simvastatin users compared to rosuvastatin users

Simvastatin users had a slower MMSE decline, compared to rosuvastatin users (0.35 more MMSE points per year of follow-up, 95% CI: 0.09; 0.61, and 1.03 more MMSE points after 3 years, 95% CI: 0.26; 1.80) (Table 4 , Fig. 5 ).

Cognitive decline, evaluated with change in MMSE scores over time, in simvastatin compared to rosuvastatin users. Linear mixed-effects regression model, adjusted for demographic characteristics, comorbidities, and co-medication, with inverse probability weighting. Yearly visit 1 represent the first MMSE measurement (baseline)

In subgroup analysis, these results remained statistically significant in women and younger patients (Supplementary table 2 ).

The associations remained protective when imputing missing MMSE values. However, incident simvastatin users had a faster decline of MMSE compared to incident rosuvastatin users (1.63 less MMSE points per year of follow-up, 95% CI: -3.18; -0.07 and 4.77 less MMSE points after 3 years, 95% CI: -9.46; -0.07) (Supplementary table 6 ).

Lipophilic statin users compared to hydrophilic statin users

We did not find significant differences in MMSE decline in lipophilic statin users (simvastatin, atorvastatin, fluvastatin users) (Table 4 ) or when considering imputed values of missing MMSE, compared to hydrophilic statins users (rosuvastatin, pravastatin users). However, it was faster in incident users of lipophilic statins (1.32 less MMSE points per year, 95% CI: -2.46; -0.18), and 3.84 less points after 3 years, 95% CI: -7.28; -0.41), compared to hydrophilic statins (Supplementary table 6 ). These analyses were not statistically significant in sub-analysis of age groups and sex (Supplementary table 3 ).

Fungal statin users compared to synthetic statin users

Use of fungal statins (simvastatin, pravastatin users) was not associated with a difference in MMSE decline compared to synthetic statin users (atorvastatin, rosuvastatin, fluvastatin users) (Table 4 ). In a subgroup analysis, the MMSE decline was slower in younger fungal statin users (0.26 more points per year, 95% CI: 0.03; 0.49, and 0.73 more points after 3 years, 95% CI: 0.05; 1.42) (Supplementary table 4 ). However, the decline was faster when analysing only incident fungal users, compared to incident synthetic users (0.61 points less per year, 95% CI: -1.19; -0.04, and 1.83 points less after 3 years, 95% CI: -3.55; -0.12) (Supplementary table 6 ).

Non-statin lipid-lowering medication users compared to statin users

We did not observe a significant difference in MMSE decline between non-statin lipid lowering medication users, compared to statin users (Table 4 ).

In some subgroup analyses, users of non-statin lipid lowering medication had a slower MMSE decline (Supplementary table 5 ).

In this longitudinal Swedish registries-based observational study of patients with AD or mixed AD dementia, we discovered a dose-dependent cognitive benefit over time in statin users compared to non-users of statins. Additionally, we discovered a slower MMSE decline over time in patients taking simvastatin, compared to either atorvastatin or rosuvastatin users. Younger users of simvastatin had a slower MMSE decline compared to younger atorvastatin users. We did not observe a difference in MMSE decline depending on lipophilicity. Incident users’ analysis revealed inconsistent findings which could be potentially explained with time-dependant non-linear association between effect of statins on cognitive processes or through differences and selection of these users.

Different statins

Simvastatin was the most used statin in Sweden when our data was collected. Accordingly, this makes comparisons among different statins or groups difficult, often lacking enough power. A beneficial role of simvastatin in early dementia is biologically plausible, when there are high levels of neuroinflammation as this lipophilic statin readily crosses the BBB and could exert various neuroprotective properties, such as protection against tau hyperphosphorylation and mediation of brain cholesterol homeostasis [ 18 ]. Research on animal models of AD further support the beneficial effects of simvastatin on cognition through different mechanisms [ 49 , 50 ]. Clinical trials in patients with mild to moderate AD reported a neutral [ 35 ] or a beneficial effect of simvastatin [ 51 ], using MMSE as a cognitive outcome. Findings were limited by relatively short trial duration and low number of participants and were therefore possibly underpowered. To our best knowledge, our study is the first observational study to compare cognitive decline between different statins in patients with established AD and mixed dementia. A careful adjustment for comedication in general and cholinesterase inhibitors in particular is important, as our group previously discovered a small long-term beneficial effect on cognition in AD and mixed dementia patients treated with cholinesterase inhibitors [ 46 ].

In our study, the analysis including only incident users showed an opposite association. A possible explanation to inconsistent results of incident user design may be related to a temporally dependent biphasic effect of statin therapy on cholesterol metabolites, as shown in a study which included asymptomatic patients at risk of AD [ 52 ]. In this study, statins initially reduced cholesterol metabolites in the cerebrospinal fluid, reaching a nadir at 6–7 months, followed by a return to baseline and an overshoot at two years. Moreover, several differences between incident users compared to all users exist which could partly contribute to the discrepancies. The individual characteristics of incident users, such as baseline MMSE differences, or a possible selection of these smaller groups of patients through individual physicians’ preferences, might have influenced their cognitive trajectories which could not be accounted for in adjusted models.

Lipophilicity and chemical characteristics (fungal or synthetic statins)

Several biochemical characteristics of statins probably influence the functional effects of statins on cholesterol metabolism and cognition. Statins with a higher lipophilicity (e.g., simvastatin, atorvastatin, fluvastatin) may cross the BBB more easily compared to more hydrophilic statins (rosuvastatin, pravastatin) [ 18 ]. Additionally, the size and orientation of a statin molecule may influence the BBB permeability of statins which explained a low ability of a lipophilic atorvastatin to cross the BBB, due to its large size [ 18 ]. In our study, we did not observe a difference in cognitive decline when comparing users of lipophilic to hydrophilic statins in most models and subgroup analyses. However, MMSE decline was faster in incident users of lipophilic statins. Due to forementioned Swedish prescription patterns, the comparisons in our study were driven by simvastatin and atorvastatin users compared to rosuvastatin users. To the best of our knowledge, we are not aware of another observational study which compared cognitive decline between lipophilic and hydrophilic statin users in AD patients.

Fungal statins (simvastatin and pravastatin) differ from the synthetic statins (atorvastatin, rosuvastatin, fluvastatin) in several functional characteristics. Synthetic statins were shown to form more interactions which leads to a stronger inhibition of HMG-CoA reductase and a higher potency [ 53 ]. Moreover, fungus-derived statins were observed to have a high permeability through the blood–brain barrier and cause a reduction of cholesterol levels as well as lower a burden of neurofibrillary tangles in animal models [ 54 ]. In our study, this comparison between fungal and synthetic statins was driven by simvastatin and atorvastatin users, so this classification did not add further information. To the best of our knowledge, no previous studies compared cognitive decline in AD or mixed dementia patients among fungal and synthetic statins. A recent cohort study comparing different incident statin users found a higher risk of AD in fungal statins compared to synthetic, as well as higher risk in lipophilic statins compared to hydrophilic statins; however, the risk was reduced in sensitivity analysis [ 55 ].

Non-statin lipid-lowering medications

The confidence intervals for this comparison were broad and did not reach statistical significance. However, MMSE decline was slower in some subgroups of non-statin lipid-lowering medications (men and younger users). Statins and other hypolipemics, such as gemfibrozil, represent another interesting comparison group since they are both prescribed for hyperlipidaemia, therefore diminishing indication bias, and could exhibit cognitive effects through different metabolic pathways. Gemfibrozil attenuated amyloid burden as well as neuroinflammation and improved the memory in AD mouse models through activation of PPAR-alpha in a recent study [ 56 ], but our study was probably underpowered for this comparison.

Statin dose, potency, treatment length and time window for intervention

The dose, potency or duration of treatment have been recognized as important factors when evaluating the effects of statins on cognition. Most work has been done on evaluating these factors in the prevention of dementia or AD [ 32 , 33 , 57 ]. A dose-response was observed in a large cohort study which included only AD patients [ 58 ]. In our study, a dose-effect was observed when comparing statin users and non-users. The prediction model showed a benefit after 3 years, which is an estimated brain cholesterol turnover rate in adults, but most of the data in our cohort aggregates towards earlier follow-ups. A time window of intervention with statins regarding the neuropathogenesis of dementia, or life course of a patient, might exist as the neurodegenerative pathological changes of AD begin decades prior to clinical symptoms [ 59 ]. The protective effect of statins could be achieved in a long-term amelioration of brain vascular burden, restoration of disturbed central cholesterol homeostasis and neuroprotective effects, possibly in preclinical [ 60 ] or early stages of AD [ 61 , 62 ].

Statin use compared to no use of statins

An extensive evaluation of the possible role of statins in preventing dementia has been performed in the last two decades [ 25 , 26 , 32 , 33 , 41 , 63 , 64 , 65 ] but comparably less studies included patients with already established AD [ 25 , 31 , 38 , 39 , 40 , 41 , 64 ]. Clinical trials of statin use in AD patients did not report a clear benefit to ameliorate cognitive decline [ 38 , 40 , 64 ]. Observational cohort studies of patients with AD and a various follow-up ranging from 10 months to over 10 years, reported a slower [ 61 , 66 , 67 , 68 ] or similar [ 69 ] cognitive decline in statins users compared to non-users. Findings from our analysis comparing statin use to no use which imply a possible dose-dependent beneficial role of statins in patients with AD is in accord with many of these previous studies. However, comparing statin users and no-users introduces several important biases.

Importantly, hyperlipidaemia is an indication for statin use in midlife and represents a risk factor for dementia and AD. On the other hand, low cholesterol level in late life has been recognized as a measure of frailty or prodromal stage of dementia, particularly AD [ 70 ]. These facts can lead an indication bias when comparing users to non-users. Secondly, clinicians might be less likely to prescribe statins to older patients, especially those with pre-existing cognitive decline, frailty, or comorbidities since the risk of possible side effects and diminished life expectancy outweighs the benefit of medication. Furthermore, cognitive impairment could lead to a discontinuation of statins or drop-out from study, which would lead to a false beneficial association [ 41 , 71 ]. Older patients who receive statins for their hypercholesterolemia could naturally possess a lower risk of dementia or reflect a better cognitive trajectory [ 72 ], leading to reverse causation.

Strengths and limitations

Our study has several strengths and limitations. We can report associations but are not able to draw the conclusions on causality. This study was meant as an exploratory analysis which requires confirmation. We considered a variety of comorbidities and comedications in our models; however, a few important covariates were not available for our analysis, such as cholesterol levels, ApoE status and possible genetic polymorphisms specific for different populations [ 73 ]. However, we addressed this issue with a selection of a population with indication for treatment and used multivariate adjusting to balance the differences between the groups as well as performed several sensitivity analyses. Patient adherence to medication was indirectly assumed based on the dispensation of medication at pharmacies. There was a considerable number of drop-out participants and missing values on MMSE. MMSE was the only measure of cognitive decline in our study and is less robust to detect cognitive changes in different cognitive domains. We chose to only include observed MMSE scores in the analyses to limit the risk of creating false data with imputation but there is, of course, a risk of selection bias. We restricted the study population to those individuals with drug use at index date to ensure that we can follow a statin user’s cognitive decline from the beginning. The results from the sensitivity analyses considering multiple imputations of MMSE are in line with our main findings and confirmed our choices. However, the results of analysis on incident users were not consistent. Another important strength of our study lies in carefully selected statistical methods. Use of linear mixed modelling with multiple imputation is currently regarded as a superior method to account for the attrition bias [ 72 ]. We considered a reasonably long follow-up and performed a large, population-based study. We examined the use of statins before dementia to explore the reverse causality of cognition influencing the adherence or use of statin but cannot completely exclude this problem with our current methods.

Our population-based exploratory cohort study of patients with AD or mixed dementia adds to a growing body of evidence that statins are not detrimental for cognition. Moreover, statins might exhibit a long-term cognitive benefit these patients who have indication for lipid-lowering treatment. However, our findings warrant a confirmational study. We believe that our findings should further encourage clinicians to select eligible patients with dementia to benefit from prevention of their cardiovascular and cerebrovascular disease with statins. Further research of the pathogenesis of dementia is warranted. Acknowledging dementia as a complex, multifactorial syndrome where different pathogenic processes and risk factors are at play at different stages of dementia, it would be plausible to examine the combined effects of several medications affecting different metabolic pathways in well-defined subtypes of dementia. Moreover, the role of lipid metabolism dysregulation to the pathogenesis of AD should be further explored, taking the genetic factors into consideration. Further research is needed to decipher the non-consistent results in incident statin users, where time since prescription may be an important factor.

Availability of data and materials

Following the Swedish and EU legislation, the data are not available for public access. In order to obtain the data from Swedish registries, researches must apply to the steering committees of the registries as well as relevant government authorities, after obtaining the ethical approval.

Abbreviations

Alzheimer’s disease

Mini-mental state examination

Swedish Registry for Cognitive/Dementia Disorders

Amyloid beta

Apolipoprotein E4

3-Hydroxy-3-methylglutaryl coenzyme A reductase

Blood–brain barrier

National Patient Registry

Swedish Prescribed Drug Registry

Defined daily dose

International Classification of Diseases, 10th Revision

Standard deviation

Confidence interval

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Acknowledgements

The authors are grateful to SveDem, www.svedem.se , for providing data for this study. We thank all patients, caregivers, reporting units and coordinators in SveDem as well as SveDem steering committee. SveDem is supported financially by the Swedish Associations of Local Authorities and Regions. Most of the statistical analyses were conducted at the Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institute, 171 77 Solna, Sweden.

Open access funding provided by Karolinska Institute. This study was supported by the regional agreement on medical training and clinical research between the Stockholm Region and the Karolinska Institutet (ALF); the Health, Medicine and Technique grants from the Stockholm Region and Kungliga Tekniska Högskolan-KTH; Swedish medical research council grant (VR) # 2022-01425 (Garcia-Ptacek) and 2020-02014 (Eriksdotter); Stiftelsen Dementia; Margaretha af Ugglas Foundation; Karolinska Institutet Research Foundation; Karolinska Institutet Foundation for Diseases of Aging; Johanniterorden i Sverige/Swedish Order of St John; the Erling Persson foundation; and by the private initiative "Innovative ways to fight Alzheimer´s disease - Leif Lundblad Family and others".

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Bojana Petek, Irena Kalar, Silvia Maioli, Bengt Winblad & Milica Gregoric Kramberger

Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia

Bojana Petek

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Bojana Petek, Irena Kalar & Milica Gregoric Kramberger

Medical Statistics Unit, Department of Learning, Informatics, Management and Ethics, Karolinska Institutet, Stockholm, Sweden

Henrike Häbel

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

Hong Xu, Marta Villa-Lopez, Minh Tuan Hoang, Shayan Mostafaei, Maria Eriksdotter & Sara Garcia-Ptacek

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Contributions

BP contributed to study design, interpretation of data, drafted and revised the manuscript. SGP designed the study, contributed to acquisition and analysis of data, drafted, and revised the manuscript, and approved the final version. HH contributed to data preparation, performed the analysis and interpretation of data, revised, and approved the final version of the manuscript. HX contributed to study design, acquisition, and interpretation of data, revised, and approved the final version of manuscript. ME contributed to data acquisition, study design, critically revised the manuscript and approved the final version of the manuscript. MVL, IK, MTH, SM, JBP, SM, BW, MGK critically revised the manuscript and approved the final version of the manuscript

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Correspondence to Bojana Petek or Sara Garcia-Ptacek .

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Ethics approval and consent to participate.

This study complies with the Declaration of Helsinki and was approved by the regional human ethics committee in Stockholm (numbers: 2015/743-31/4 and 2017/942-32). All patients and their relatives were informed of inclusion in SveDem at the time of diagnosis and had the right to decline the participation or withdraw the data from the registry at any point. The data were de-identified before analysis.

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SGP holds stock in AstraZeneca, Bioarctic, Calliditas, Camurus, Dynavax, Moderna, Novo Nordisk, Pfizer, Sanofi, and Vicore. The other authors report no conflicts of interest.

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Supplementary Information

Additional file 1:.

Supplementary table 1. Cognitive decline in subgroups of statins users vs users of non-users of statins. Supplementary table 2. Cognitive decline in subgroups of simvastatin users vs rosuvastatin users. Supplementary table 3. Cognitive decline in subgroups of lipophilic statins users vs hydrophilic statins users. Supplementary table 4. Cognitive decline in subgroups of fungal statins users vs synthetic statins users. Supplementary table 5. Cognitive decline in subgroups of non-statin lipid-lowering medication users vs statins users. Supplementary table 6. Cognitive decline in different treatment groups, sensitivity analysis. Supplementary table 7. Characteristics of incident users.

ICD-10 codes for comorbidities

Diabetes mellitus/insulin/other antidiabetics (E1[0-4] A10A A10B), arrhythmia (I49), alcohol-related disease (E244 F10 G312 G621 G721 I426 K292 K70 K860 O354 P043 Q860 T51 Y90 Y91 Z502 Z714), chronic kidney disease (N18 N19 I120 I131 N032 N033 N034 N035 N036 N037 N052 N053 N054 N055 N056 N057 N18 N19 N250 T856 T857 Z490 Z491 Z492 Z940 Z992), heart failure (I500, I501, I509), cardiovascular disease (I21[0-4] I219 I220 I221 I228 I229 I25 I63 I739 I70), myocardial infarction (I21 I22 I252), respiratory disease (J4[0-7] J6[0-7] J684 J701 J703), haemorrhagic stroke (I60 I61 I62), other stroke (I63 I64 I69), anaemia (D50 D62), liver failure (K7), ischemic heart disease (I20 I21 I22 I23 I24 I25), malignancy (C[0-9][0-9] D[1-3]D4[0-8]) and obesity (E66).

ATC codes for lipid-lowering medication

Simvastatin (C10AA01 C10BA02 C10BX01 C10BX04), atorvastatin (C10AA05 C10BA05 C10BX03, C10BX06 C10BX08 C10BX11 C10BX12 C10BX15), pravastatin (C10AA03), fluvastatin (C10AA04), rosuvastatin (C10AA07 C10BA06 C10BX05 C10BX07 C10BX09 C10BX10 C10BX13 C10BX14), pitavastatin (C10AA08), fibrates (C10AB), bile acid sequestrants (C10AC), nicotinic acid and derivates (C10AD) and other lipid modifying agents (C10AX).

ATC codes for comedication

Cardiac drugs (C01), vasoprotectives (C05), platelet aggregation inhibitors (B01AC), anticoagulants (B01AA B01AB B01AF B01AE07), antipsychotics (N05A), anxiolytics (N05B), hypnotics (N05C), antidepressants (N06A), anticholinesterases (N06DA), memantine (N06DX01) and vitamin D (A11CC).

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Petek, B., Häbel, H., Xu, H. et al. Statins and cognitive decline in patients with Alzheimer’s and mixed dementia: a longitudinal registry-based cohort study. Alz Res Therapy 15 , 220 (2023). https://doi.org/10.1186/s13195-023-01360-0

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DOI : https://doi.org/10.1186/s13195-023-01360-0

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Hundreds of thousands face being denied revolutionary new dementia drugs in England

Exclusive: Treatments near approval but lack of diagnostic capacity means NHS unprepared for rollout, report says

What are the symptoms of dementia and how do you get a diagnosis?

Hundreds of thousands of dementia patients in England face being denied access to revolutionary new drugs because the diagnostic capacity of the NHS lags behind every other G7 country, according to a damning report.

After decades of research to find a cure for the condition projected to affect 153 million people worldwide by 2050, scientists have successfully developed the first treatments to tackle the underlying causes rather than only relieve the symptoms. Two new drugs could get the green light for use on the NHS within weeks.

However, their effectiveness depends on prompt and early diagnosis of patients . The report, obtained by the Guardian, says the NHS lacks the diagnostic capacity to accurately identify those eligible in time.

The analysis reveals England is unprepared for the rollout of new treatments, with “large gaps in diagnostic capacity” for dementia. It also warns of a £14bn funding black hole that must be plugged if England is to diagnose dementia as quickly as the other G7 countries, the US, Canada, France, Germany, Italy and Japan.

To be eligible for either of the new drugs, lecanemab and donanemab, patients have to be in the early stages of dementia and have had scans to confirm high levels of amyloid in their brain. However, the report says England has the lowest per capita number of PET scanners of any G7 country and the lowest number of MRI scanners. England also has the second-lowest number of dementia specialists needed to diagnose the condition, such as neurologists, old age psychiatrists and geriatricians.

The analysis was produced by experts from organisations including Alzheimer’s Research UK, Alzheimer’s Disease International and the Alzheimer’s Society.

A second study, an NHS briefing paper also seen by the Guardian, estimates that as many as 280,000 patients in England may be eligible for the new treatments if regulators recommend the drugs for use in the health service. However, if the treatments are approved, the NHS would be unprepared for their delivery, the first report says.

“The potential approval of the first of the disease-modifying AD [Alzheimer’s disease] treatments in the UK as early as 2024, and the prospect of subsequent availability in England, shines a light on the stark gap in diagnostic infrastructure needed to provide high-quality dementia care,” it says.

“While future detection and diagnostic technologies might allow for lowering investment levels in later years compared to our projections, the progressive nature of AD means that prolonged wait times would deprive numerous patients of the opportunity to receive a treatment while it will still be effective.”

Dr Susan Mitchell, the head of policy at Alzheimer’s Research UK and a co-author of the report, told the Guardian the NHS had “suffered years of under-investment in diagnostics” and as a result dementia patients were “being left to fall through the cracks”.

“When it comes to diagnosing dementia, timing is everything. Yet right now, too many people are anxiously waiting to get a brain scan or speak to a specialist, and this is stopping them from getting the care and support they deserve. If new Alzheimer’s treatments are approved by regulators, delays to diagnosis could also hurt people’s chances of accessing them, as they are thought to be most effective for those who are in the disease’s earliest stages.”

The most recent NHS figures show fewer than two-thirds of people with dementia (64.5%) have a formal diagnosis – below the government’s target of 67%. People in England wait on average up to two years to receive a diagnosis, and up to four years if under 65.

For the report, the authors compared data and statistics for England with that of the six other countries in the G7. The report found England had the lowest number of PET scanners per 1 million people, at 1.20. Canada has 1.52, Germany has 1.63, France has 2.48, Italy has 3.55, Japan has 4.70, and the US has 5.45.

England also has the lowest number of MRI scanners per 1 million people (6.31), while Canada has 10.06, France has 15.38, Italy has 30.22, Germany has 34.47, the US has 40.44, and Japan has 55.21.

When it comes to dementia specialists, England also fares badly, with 5.04 per 100,000 people, according to the report. Only Canada has a worse record (4.94). France has 6.46, the US has 8.82, Japan has 11.08, and Italy has 15.58. Germany has almost five times as many as England (24.02).

It is estimated that only 2% of people getting a dementia diagnosis in England have access to gold standard tests, the report says.

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NHS England officials said dementia diagnosis rates were at their highest for three years. Staff had worked hard to recover services after the Covid-19 crisis when people were less likely to come forward for care, they said.

Mitchell said that without an overhaul of the diagnosis system, people in the earliest stages of dementia could be at risk of missing out on the first-of-a-kind treatments.

“It will be impossible to improve either early or accurate diagnosis without addressing gaps in the workforce and infrastructure – and this research shows just how far England has to go,” she said. “It is shocking to see us sitting at the bottom of the G7 tables for PET and MRI capacity, and only slightly better in terms of staffing. Investment in NHS staff, equipment and facilities is needed to turn the tide.”

The number of people living with dementia in the UK is predicted to rise from 944,000 to 1.6 million by 2050. “This is a crisis that should be at the top of the prime minister’s priority list,” said Mitchell.

The Department of Health and Social Care said it was working to identify and treat more people with dementia, and offer new treatments as they became available.

A spokesperson said: “NHS England is working on improving dementia diagnosis in care homes and taking steps to secure additional diagnostic capacity, including MRI, lumbar puncture and PET-CT scanners.”

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March 27, 2024

Does Long-Term Benadryl Use Increase Dementia Risk?

Benadryl, which contains diphenhydramine, is a drugstore mainstay and just one medication out of many that could possibly damage brain health

By Hannah Seo

John Kuczala/Getty Images

In the past few months TikTok videos about the over-the-counter antihistamine Benadryl have gone viral because of research suggesting that long-term use of the popular drug is associated with an increased risk of developing dementia. And similar effects on memory and cognition have also been suggested for dozens of other common medications.

Benadryl is a brand-name medication that contains diphenhydramine, the active ingredient in many allergy, cold and anti-itch drugs. It can cause significant drowsiness and is also found in several sleep aids. Diphenhydramine has anticholinergic effects, meaning it blocks the action of a neurotransmitter called acetylcholine. Medical uses of anticholinergics go beyond allergy relief; drugs in this class have long been used as prescription tricyclic antidepressants and incontinence treatments, as well as over-the-counter sleep aids. But experts have been finding evidence that links anticholinergics to increased dementia risks. “That’s now clear, and we have plenty of data to back it up,” says Malaz Boustani, a geriatrician and neuroscientist at the Indiana University School of Medicine. He and other researchers are now trying to determine whether anticholinergics really are contributing to dementia development in any way—and if so, what exactly is happening in the brains of vulnerable adults.

Anticholinergics inhibit the parasympathetic nervous system , which regulates rest and stress responses. The drugs do this by binding to brain cell receptors and blocking acetylcholine, a neurotransmitter that plays a part in many bodily systems, including heart regulation, muscle contractions, urination and digestion. Acetylcholine also affects attention and memory—and a lack of the neurotransmitter in the brain has been linked to Alzheimer’s disease . When bound to receptors, anticholinergics prevent acetylcholine from acting on the parasympathetic nervous system, often causing effects such as dry mouth. These medications can also make people groggy by blocking histamine receptors, which are involved in alertness as well as allergies. Side effects should fade once the drug is out of someone’s system (which in Benadryl’s case would be within a couple of days). But Boustani says less is known about the effects of regular or heavy use.

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A 2015 paper in JAMA Internal Medicine offered some striking insight into possible long-term effects. The hallmark study—which became the basis for the recent viral TikToks—observed adults 65 years or older who had been taking various kinds and amounts of anticholinergic drugs for 10 years. The group reporting the highest amount of such use had a 54 percent increased risk of developing dementia. Since the study, a steady stream of new research has corroborated this link.

The studies show an association between dementia risk and the quantity and frequency of anticholinergic use. One capsule of Benadryl to relieve an allergy every once in a while probably won’t affect someone all that much, but repeated doses of anticholinergic drugs over months or years pose a greater risk, Boustani says. Taking multiple anticholinergics for multiple conditions may also increase your exposure and could raise the risk further, he adds. Another consideration is that some of these drugs have more potent effects than others. Boustani’s team created the Anticholinergic Cognitive Burden (ACB) Scale , a list of drugs with scores based on their potential negative effects on the brain. The scale goes from 1 (possibly an anticholinergic burden) to 3 (definitely a strong anticholinergic burden), Boustani says. For example, someone taking three anticholinergic drugs, all with a score of 1, will have a total anticholinergic cognitive burden score of 3. Boustani says that person may see roughly the same cumulative effects as someone who just takes one anticholinergic with a score of 3. There are currently no protocols or recommendations for doctors and pharmacists to consider a person’s ACB score when prescribing drugs. But the American Geriatrics Society maintains a list of drugs older people should avoid, and it does include many anticholinergic medications.

Researchers are still digging into the specific brain mechanisms that may be involved in elevated dementia risk from these drugs, Boustani says. A leading hypothesis suggests this might be related to how the drugs interact with neurotransmitter receptors. Long-term anticholinergic use might leave acetylcholine receptors perpetually blocked, triggering a series of reactions that either leads to the production of beta-amyloid—a toxic protein thought to be a main cause of dementia—or prevents the brain from clearing this protein out. Researchers have suggested these drugs might affect inflammation and blood flow in the brain, which may result in memory loss and weakened cognition. But so far this research is inconclusive.

Some experts are skeptical that anticholinergics play a role in developing dementia; they suspect the drugs may instead worsen underlying cognitive issues. Ariel Gildengers, a psychiatrist at the University of Pittsburgh, led a 2023 study that did not show a link between anticholinergics and developing dementia. But it did show a link between the drugs and mild cognitive impairment (MCI), a condition in which people have worse cognitive function than expected at their age but do not meet the criteria for dementia. And MCI does have a noticeable chance of turning into dementia. About 10 to 15 percent of people living with MCI develop dementia each year, according to the Alzheimer’s Association . “If you are in the earliest stages of dementia, then anticholinergics may kind of make the dementia more apparent without actually causing the dementia,” Gildengers says.

Research in this area has several major caveats, says Shelly Gray, a pharmacy professor at the University of Washington, who was the first author of the 2015 JAMA paper. “We cannot determine that anticholinergics actually cause dementia” because the 2015 study and others on the relationship have been observational, she says. Clinical trials are needed to confirm causation. Most of these studies are also done in adults aged 65 and older, who are more likely to develop dementia than younger adults and more likely to face medical conditions such as insomnia, which are often treated with anticholinergics. Gray, Boustani and Gildengers say that they keep these possible confounding factors in mind when they design and analyze their studies.

Because research has focused mostly on older adults, there is less evidence on whether younger people who take anticholinergics have increased risk of dementia later in life. Gray says it’s generally a good idea to avoid anticholinergics, however, especially if you’re older. “A big reason why we're seeing anticholinergic medications used by older adults is because they are available over the counter,” Gray says. Many readily available medications have anticholinergic active ingredients, including Benadryl, as well as the antihistamine Dimetapp (which contains the drug brompheniramine), the motion sickness medication Dramamine (dimenhydrinate) and the sleep aid Unisom (doxylamine).

Many anticholinergics can be swapped with other options, Gray says. For example, studies show that cognitive behavioral therapy is often effective for insomnia. "Second-generation antihistamines,” such as those in Claritin and Zyrtec, along with steroid-based nasal sprays such as Flonase, will counteract allergy symptoms without targeting acetylcholine receptors—says Jyothi Tirumalasetty, a clinical assistant professor of medicine at Stanford University, who specializes in allergy and immunology.

The Food and Drug Administration first approved Benadryl as a prescription antihistamine in 1946 and for over-the-counter sales in 1980s. Given the research on potential risks, Tirumalasetty says the FDA might evaluate the drug’s safety differently today and may consider making it available only through prescription. The FDA did not respond to a request for comment by the time of publication . In an e-mail to Scientific American, Kenvue (formerly a division of Johnson & Johnson and Benadryl’s current proprietor) wrote, “We are not aware of any studies that show a causal link between labeled use of diphenhydramine, and an increased risk of developing dementia. Diphenhydramine is an ingredient which is generally recognized as safe and effective by the FDA for [over-the-counter] use.”

Researchers are continuing to investigate anticholinergics and their possible long-term effects on brain health, hoping to help with future clinical and regulation guidance. Boustani says many questions persist, such as how the timing of taking or discontinuing these drugs affects the development of future memory problems.

For now, Boustani is focused on empowering his patients, especially older adults, with the ability to understand their medications and any attendant risks. He says people taking or considering an anticholinergic at any age should ask themselves a few questions: “Are there any alternatives? What symptoms am I addressing, and is alleviating them worth this risk? What is the smallest dose and time period I can take this medication for?”

“The brain is a precious organ,” Boustani says. “There is no health without brain health.”

Thousands of people to trial Alzheimer's blood tests

Memory clinics across the UK are to begin trialling blood tests to see if they can accurately diagnose dementia.

The hope is that more people will be able to access care, support and new drug treatments at an earlier stage.

The research, by University College London and the University of Oxford, will involve around 5,000 volunteers.

The five-year project will study blood tests for Alzheimer's disease and other forms of dementia.

Currently, around a third of patients with dementia never get a formal diagnosis and are left with worry and uncertainty about their condition.

Rogue proteins

Only around 2% of patients have one of the 'gold standard' tests for Alzheimer's - either a specialist PET brain scan or a spinal lumbar puncture.

Both can show the presence of rogue proteins in the brain such as amyloid and tau which start to accumulate up to 20 years before symptoms emerge - but tests are expensive.

The Oxford team will be looking at a range of blood tests, which could be a cheaper and easier way for doctors to spot early signs of the disease.

One blood test will look for traces of these proteins in the blood in order to diagnose Alzheimer's disease, the most common form of dementia. Some tests will also look for potential biomarkers for vascular and frontotemporal dementia, and dementia with Lewy bodies.

The researchers will also look at whether the blood tests can help detect these diseases at various stages.

NHS 'not ready' for new Alzheimer's drugs

NHS exploring Alzheimer's disease blood tests

How common is early Alzheimer's?

Dr Vanessa Raymont, from the University of Oxford, is leading a study which will recruit volunteers from more than 50 UK trial sites, which are all NHS memory clinics.

She told the BBC that although several dementia blood tests had already shown promising results, they had limitations.

"Research has tended to exclude the very elderly, ethnic minorities and those with other medical conditions so we need to understand what the data looks like in the real world, which is why these projects are so important."

The University College London (UCL) team will focus on the most promising biomarker for Alzheimer's disease, called p-tau217, which can indicate levels of amyloid and tau in the brain.

Its trial will see if measuring p-tau217 in the blood can increase the rate of diagnosis for Alzheimer's disease in people with early dementia, but also those with mild but progressive memory problems.

Access to new treatments

Jonathan Schott, professor of neurology at UCL, who is leading the trial, said: "An early, accurate diagnosis of Alzheimer's disease is already important, allowing people to access appropriate care and medications.

"If, as we hope, new treatments that can slow down Alzheimer's disease become available soon, then this will be vital," he said.

"This would pave the way for fair and equitable access to new and potentially life-changing treatments to all who might benefit."

Two treatments have shown in trials that they can slow the progression of early stage Alzheimer's. Doctors say the benefits are modest but they represent the first 'disease-modifying' drugs.

The drugs, lecanemab and donanemab, are currently being considered by the MHRA, the body which approves drugs in the UK.

Even if they are granted licences, they would then need to be given the green light by health assessment bodies which consider their cost-effectiveness for the NHS, before being rolled out to patients.

Dr Sheona Scales, director of research at Alzheimer's Research UK, said: "We've seen the enormous potential that blood tests are showing for improving the diagnostic process for people and their loved ones in other disease areas."

She said it was important to see "the same step-change in dementia", which is the greatest health challenge facing the UK.

The Blood Biomarker Challenge is being funded by Alzheimer's Society, Alzheimer's Research UK, the National Institute for Health and Research and Gates Ventures, including £5m from People's Postcode Lottery.