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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.

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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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We may finally know what causes Alzheimer’s – and how to stop it

By Debora Mackenzie

23 January 2019 , updated 30 January 2019

Alzheimer’s disease has destroyed neurons in the right-hand brain above

Jessica Wilson/Science Photo Library

AFTER decades of disappointment, we may have a new lead on fighting Alzheimer’s disease. Compelling evidence that the condition is caused by a bacterium involved in gum disease could prove a game-changer in tackling one of medicine’s biggest mysteries, and lead to effective treatments or even a vaccine.

As populations have aged, dementia has skyrocketed to become the fifth biggest cause of death worldwide. Alzheimer’s constitutes some 70 per cent of these cases (see “ What is Alzheimer’s disease ”), yet we don’t know what causes it. The condition, which results in progressive loss of memory and cognitive function, usually over a decade or so, is devastating both to those who have it and to their loved ones.

The condition often involves the accumulation of two types of proteins – called amyloid and tau – in the brain. As these are among the earliest physical signs of the disease, the leading hypothesis since 1984 has been that the condition is caused by the defective control of these proteins, especially amyloid, which accumulates to form large, sticky plaques in the brain.

The bulk of research into understanding and treating Alzheimer’s has centred on this “amyloid hypothesis”. Huge sums of money have been invested in experiments involving mice genetically modified to produce amyloid, and in developing drugs that block or destroy amyloid proteins, or sometimes degraded tangles of tau.

It has become clear that this approach isn’t working. In 2018 alone, the US National Institutes of Health spent $1.9 billion on Alzheimer’s research. But according to a recent study , the failure rate of drug development for Alzheimer’s has been 99 per cent.

Some have begun to question the amyloid hypothesis . The lack of results has been compounded by the discovery that people – including some in their 90s with exceptional memories – can have brain plaques and tangles without having dementia. In a review of the research to date last year, Bryce Vissel at the University of Technology Sydney, Australia, concluded that there isn’t sufficient data to suggest that “amyloid has a central or unique role in Alzheimer’s”.

“The bacteria in the brain are not the result of Alzheimer’s, but they could be the cause”

In 2016, researchers discovered that amyloid seems to function as a sticky defence against bacteria. They found that the protein can act as an anti-microbial compound that kills bacteria, and when they injected bacteria into the brains of mice engineered to make Alzheimer’s proteins, plaques developed round bacterial cells overnight.

Accompany Richard Dawkins around Hawaii: Sailing on a New Scientist Discovery Tour

At the time, the team said it still believed that amyloid itself went on to cause the brain damage of Alzheimer’s, not bacteria. But a spate of subsequent studies have looked at microbes . Bacteria have been found in the brains of people who had Alzheimer’s when they were alive. But it hasn’t been clear whether the bacteria caused the disease or were simply able to enter brains damaged by Alzheimer’s.

Multiple teams have been researching Porphyromonas gingivalis, the main bacterium involved in gum disease , which is a known risk factor for Alzheimer’s. So far, teams have found that P. gingivalis invades and inflames brain regions affected by Alzheimer’s; that gum infections can worsen symptoms in mice genetically engineered to have Alzheimer’s; and that it can cause Alzheimer’s-like brain inflammation, neural damage and amyloid plaques in healthy mice .

A whole new hypothesis

“When science converges from multiple independent laboratories like this, it is very compelling,” says Casey Lynch of Cortexyme, a pharmaceutical firm in San Francisco.

Now researchers from Cortexyme and several universities have reported finding the two toxic enzymes that P. gingivalis uses to feed on human tissue in 99 and 96 per cent of 54 human Alzheimer’s brain samples taken from the hippocampus – a brain area important for memory ( Science Advances , doi.org/gftvdt ). These protein-degrading enzymes are called gingipains, and they were found in higher levels in brain tissue that also had more tau fragments and thus more cognitive decline.

The team also found genetic material from P. gingivalis in the cerebral cortex – a region involved in conceptual thinking – in all three Alzheimer’s brains they looked for it in.

“This is the first report showing P. gingivalis DNA in human brains, and the associated gingipains co-localising with plaques,” says Sim Singhrao at the University of Central Lancashire, UK, who wasn’t involved in the study. Her team has previously found that P. gingivalis actively invades the brains of mice with gum infections.

When Lynch and her colleagues looked at brain samples from people without Alzheimer’s, they saw that some had P. gingivalis and protein accumulations, but at low levels. We already know that amyloid and tau can accumulate in the brain for 10 or 20 years before Alzheimer’s symptoms begin. This, says the team, shows that P. gingivalis doesn’t get into the brain as a result of Alzheimer’s – but could be the cause.

The Porphyromonas gingivalis bacteria that can cause gum disease

A. Dowsett, Public Health England/Science Photo Library

When the team gave P. gingivalis gum disease to mice, it led to brain infection, amyloid production, tangles of tau protein and neural damage in the regions and nerves normally affected by Alzheimer’s. This suggests causation, says Lynch.

She adds that P. gingivalis fulfils an updated set of criteria for attributing a disease to a particular pathogen. These conditions are named Koch’s postulates, after Robert Koch , a founder of the germ theory of disease.

“The study does address most of Koch’s postulates,” says Robert Genco of the University at Buffalo, New York. “Future studies need to be in humans to be convincing.”

We don’t know how P. gingivalis gets into the brain, but there are plausible routes it could take. Your mouth normally hosts a diverse and relatively stable community of bacteria, but when dental plaque builds under the edge of your gums, it can form inflamed pockets in which P. gingivalis can thrive and release toxins.

Read more: Here’s how to avoid gum disease

This inflammation can lead to chronic periodontitis and tooth loss , and some studies have shown that people with fewer teeth are more likely to have dementia . The inflammation and toxins caused by P. gingivalis damage the lining of your mouth, which may make it possible for oral bacteria to enter the bloodstream and then other organs. Even if you don’t have gum disease, transient damage to your mouth lining from eating or tooth-brushing can let mouth bacteria into your blood, says Lynch.

The blood-brain barrier should protect your brain from microbes, but P. gingivalis can invade white blood cells and the cells lining blood vessels, so might cross it that way. It may also invade cranial nerves near the mouth, then spread from cell to cell towards the brain over a period of years.

“This is why years of efforts to treat Alzheimer’s have seen few results”

As to how P. gingivalis might cause dementia after it arrives in the brain, there are two clear possibilities. It may trigger the release of amyloid, the brain’s method of trying to contain the infection, and this may then kill neurons.

Or P. gingivalis may directly damage the brain. We already know that Alzheimer’s involves inflammation, an excessive immune response that ends up killing neurons instead of protecting them. P. gingivalis is known to cause inflammation in gum tissue, and it may do so in the brain as well.

In response to the new findings, David Reynolds of the Alzheimer’s UK charity said he is dubious that P. gingivalis causes Alzheimer’s, because of the evidence showing that a person’s genes play a crucial role in the disease. “Strong genetic evidence indicates that factors other than bacterial infections are central to the development of Alzheimer’s, so these new findings need to be taken in the context of this existing research,” he said in a statement.

Read more: Wake-up call: How a lack of sleep can cause Alzheimer’s

But a bacterial hypothesis for Alzheimer’s doesn’t conflict with genetic evidence. The human body’s propensity for inflammation can vary according to genetic variations that affect our immune systems, and this may influence how much damage P. gingivalis induces in a brain.

The biggest genetic risk factor for Alzheimer’s is a variant of the gene that makes the ApoE immune protein. Last year, a team in Sweden found that the gingipains released by P. gingivalis break up the ApoE protein into fragments, cleaving it at the site of a particular amino acid within the protein, and that these fragments may harm nerves. The ApoE4 variant of this protein contains more of this amino acid, suggesting that the reason people who make this variant are at a higher risk of developing Alzheimer’s may be because harmful levels of ApoE protein fragments build up more quickly in their brains than in those of other people.

Hope for treatments

The speed at which damage accumulates is a key factor in the disease. Although many people harbour P. gingivalis in their mouths, only some develop Alzheimer’s. Because it can be decades before Alzheimer’s symptoms appear, whether a person develops the condition could come down to how much damage occurs before they die of other causes.

“Alzheimer’s strikes people who accumulate gingipains and damage in the brain fast enough to develop symptoms during their lifetimes,” says Lynch. She says her team’s findings are a “universal hypothesis of pathogenesis”, fully explaining the causes of Alzheimer’s disease.

But Vissel warns that Alzheimer’s is a complex disease. “The answer is unlikely to be one-cause-fits-all. We need to keep open eyes.”

However, the new study is “very exciting”, he says. “Alzheimer’s is so common in people at advanced age that I think it can only be either some intrinsic property of the brain, or an infection.”

If this new hypothesis of Alzheimer’s is borne out, the good news is that it could lead to effective treatments for the condition. Although there is plenty you can do to reduce your risk of gum disease, Cortexyme is hoping it can stop or even reverse Alzheimer’s using molecules it has developed that block gingipains. The firm found that giving some of these to mice with P. gingivalis infections reduced brain infection, halted amyloid production, lowered brain inflammation and even rescued damaged neurons. “This provides hope of treating or preventing Alzheimer’s disease one day,” says Singhrao.

Read more: The Alzheimer’s problem: Why we are struggling to find a cure

Cortexyme reported last year that the best of its gingipain blockers had passed initial safety tests in people, and entered the brain. It also seemed to improve symptoms in participants with Alzheimer’s. The firm will launch a larger trial later this year.

The company also plans to test the drug against gum disease itself. Efforts to fight that have led a team in Melbourne to develop a vaccine for P. gingivalis that started tests in 2018 . A vaccine for gum disease would be welcome – and if it also stops Alzheimer’s the impact could be enormous.

It is early days for this new hypothesis, and if the pursuit of amyloid-busting drugs over the past few decades has taught us anything, says Vissel, it is that a complex disease may not have a simple mechanism. Even if P. gingivalis is confirmed as a cause of Alzheimer’s, we don’t know yet whether it will turn out to be the only cause or one of several factors contributing to the disease.

“This paper is very important,” says George Perry at the University of Texas at San Antonio. “The view that pathogens might be one of several paths leading to Alzheimer’s disease fits my current thoughts of amyloid and tau being critical brain responses to injury, instead of the initiators.”

That, he says, is why years of efforts to treat Alzheimer’s by removing those proteins have seen few results: they are symptoms of the disease, not its cause. “This is a further turning point in the understanding that infections and inflammation can be at the heart of Alzheimer’s disease.”

What is Alzheimer’s disease?

There are many types and causes of dementia, but Alzheimer’s disease is the most common form, accounting for between 60 and 70 per cent of all cases.

Common early symptoms of Alzheimer’s include short-term memory loss, apathy and depressed mood, but these symptoms are often just seen as being a part of normal ageing, making early diagnosis difficult.

Doctors diagnose Alzheimer’s on the basis of medical examination, patient history and cognitive tests, and can use imaging to rule out other forms of dementia. However, a definitive diagnosis of Alzheimer’s is only possible after death, when examination of brain tissue can reveal whether a person had the deposits of amyloid and tau proteins (see main story) that are characteristic of the condition.

The vast majority of people with Alzheimer’s are diagnosed with the condition after the age of 65, but clumps of amyloid protein can begin to build up in the brain some 15 or 20 years before symptoms appear. We have long hoped for diagnostic tests that can determine if someone has Alzheimer’s before death, and spot the condition before extensive brain damage has occurred. Donna Lu

Bad bacteria and other microbes

It might seem surprising that a mouth bacterium has been implicated in Alzheimer’s disease (see main story). But it wouldn’t be the first time an illness has turned out to have an unexpected infectious origin.

The iconic case is stomach ulcers, once thought to be caused by stress or excess acid, and treated with acid-lowering medications. Then Australian doctor Barry Marshall showed that a stomach bacterium called Helicobacter pylori was behind them, a feat that won him a Nobel prize.

Streptococcus bacteria, which cause tonsillitis and “strep throat”, are suspected of triggering obsessive-compulsive disorder in children. The thinking is that the immune system’s attack on the bacteria cross-reacts with certain human proteins, causing an autoimmune attack against the person’s own brain tissue.

Bacteria aren’t the only ones under suspicion. There are indications that a virus is behind some cases of obesity. And one study has found that people with antibodies to a single-celled brain parasite called Toxoplasma gondii , which is spread in cat faeces, are more likely to develop schizophrenia. Some people think up to a third of cases could be caused by infection with T. gondii .

But not all purported links bear fruit. Twenty years ago, there was great excitement when a bacterium that can cause pneumonia lung infections was found in the blood vessel plaques that cause heart disease. But giving people antibiotics to kill this bug didn’t help reduce heart attacks. Clare Wilson

Science Advances DOI: 10.1126/sciadv.aau3333

This article was updated on 30 January 2019 to add more detail and comment

Article amended on 24 January 2019

• mental health /
• Alzheimer’s

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New cause of Alzheimer's, vascular dementia

Study highlights microglia degeneration in brain caused by iron toxicity.

Researchers have discovered a new avenue of cell death in Alzheimer's disease and vascular dementia.

A new study, led by scientists at Oregon Health & Science University and published online in the journal Annals of Neurology on Aug. 21, reveals for the first time that a form of cell death known as ferroptosis -- caused by a buildup of iron in cells -- destroys microglia cells, a type of cell involved in the brain's immune response, in cases of Alzheimer's and vascular dementia.

The researchers conducted the study examining post-mortem human brain tissue of patients with dementia.

"This is a major finding," said senior author Stephen Back, M.D., Ph.D., a neuroscientist and professor of pediatrics in the OHSU School of Medicine.

Back has long studied myelin, the insulation-like protective sheath covering nerve fibers in the brain, including delays in forming myelin in premature infants. The new research extends that line of work by uncovering a cascading form of neurodegeneration triggered by deterioration of myelin. They made the discovery using a novel technique developed by the study's lead author Philip Adeniyi, Ph.D., a postdoctoral researcher in Back's laboratory.

The researchers discovered that microglia degenerates in the white matter of the brain of patients with Alzheimer's and vascular dementia.

Microglia are resident cells in the brain normally involved in clearing cellular debris as part of the body's immune system. When myelin is damaged, microglia swarm in to clear the debris. In the new study, researchers found that microglia themselves are destroyed by the act of clearing iron-rich myelin -- a form of cell death known as ferroptosis.

Given the intense scientific focus on the underlying cause of dementia in older adults, Back called it amazing that researchers hadn't made the connection to ferroptosis until now.

"We've missed a major form of cell death in Alzheimer's disease and vascular dementia," Back said. "We hadn't been giving much attention to microglia as vulnerable cells, and white matter injury in the brain has received relatively little attention."

Co-author Kiera Degener-O'Brien, M.D., initially discovered the degeneration of microglia in tissue samples, Back said. Adeniyi subsequently developed a novel immunofluorescence technique to determine that iron toxicity was causing microglial degeneration in the brain. This was likely a result of the fact that the fragments of myelin are themselves rich in iron, Back said.

In effect, the immune cells were dying in the line of duty.

"Everyone knows that microglia are activated to mediate inflammation," Back said. "But no one knew that they were dying in such large numbers. It's just amazing that we missed this until now."

The study finds that the cascading effect of degenerating microglia appears to be a mechanism in advancing cognitive decline in Alzheimer's disease and vascular dementia, Back said. He expects pharmaceutical companies will use this new finding to develop compounds focused on reducing microglial degeneration in the brain.

"That's where the field will go next," he said. "A discovery like ours will stimulate a lot of excitement in the pharmaceutical industry to develop therapeutically important compounds."

He said the underlying cause initiating the cycle of decline likely relates to repeated episodes of low blood flow and oxygen delivery to the brain over time due to acute stroke or chronic conditions such as hypertension and diabetes.

"Dementia is a process that goes on for years and years," Back said. "We have to tackle this from the early days to have an impact so that it doesn't spin out of control."

The research was supported by grants from the National Institute on Aging (AG065406, AG031892, U01 AG006781, and U19 AG066567 which supports the ACT study, p50 AG005136 and p30AG066509, which support the UW Alzheimer's disease Research Center) of the National Institutes of Health; the National Institute of Neurological Disorders and Stroke of the NIH (NS105984); and by the Nancy and Buster Alvord Endowment. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Story Source:

Materials provided by Oregon Health & Science University . Original written by Erik Robinson. Note: Content may be edited for style and length.

Journal Reference :

• Philip A. Adeniyi, Xi Gong, Ellie MacGregor, Kiera Degener‐O'Brien, Evelyn McClendon, Mariel Garcia, Oscar Romero, Joshua Russell, Taasin Srivastava, Jeremy Miller, C. Dirk Keene, Stephen A. Back. Ferroptosis of microglia in aging human white matter injury . Annals of Neurology , 2023; DOI: 10.1002/ana.26770

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Scientists discover potential cause of Alzheimer’s Disease

Existing drugs may offer effective prevention

Prevailing theories posit plaques in the brain cause Alzheimer’s disease. New UC Riverside research instead points to cells’ slowing ability to clean themselves as the likely cause of unhealthy brain buildup. 

Along with signs of dementia, doctors make a definitive Alzheimer’s diagnosis if they find a combination of two things in the brain: amyloid plaques and neurofibrillary tangles. The plaques are a buildup of amyloid peptides, and the tangles are mostly made of a protein called tau. 

“Roughly 20% of people have the plaques, but no signs of dementia,” said UCR Chemistry Professor Ryan Julian. “This makes it seem as though the plaques themselves are not the cause.” 

For this reason, Julian and his colleagues investigated understudied aspects of tau protein. They wanted to understand whether a close examination of tau could reveal more about the mechanism behind the plaques and tangles. 

A key but difficult-to-detect difference in the form of tau allowed the scientists to distinguish between people who expressed no outward signs of dementia from those who did. These results have now been published in the Journal of Proteome Research. 

Julian’s lab focuses on the different forms that a single molecule can take, called isomers. 

“An isomer is the same molecule with a different three-dimensional orientation than the original,” Julian said. “A common example would be hands. Hands are isomers of each other, mirror images but not exact copies. Isomers can actually have a handedness.”

The amino acids that make up proteins can either be right-handed or left-handed isomers. Normally, Julian said, proteins in living things are made from all left-handed amino acids.

For this project, the researchers scanned all the proteins in donated brain samples. Those with brain buildup but no dementia had normal tau while a different-handed form of tau was found in those who developed plaques or tangles as well as dementia.

Most proteins in the body have a half-life of less than 48 hours. However, if the protein hangs out too long, certain amino acids can convert into the other-handed isomer. 

“If you try to put a right-handed glove on your left hand, it doesn’t work too well. It’s a similar problem in biology; molecules don’t work the way they’re supposed to after a while because a left-handed glove can actually convert into a right-handed glove that doesn’t fit,” Julian said.

In general, the process of clearing spent or defective proteins from cells, known as autophagy, slows down in people over the age of 65. It isn’t clear why, but Julian’s laboratory is planning to study this. 

Fortunately, drugs are already being tested to improve autophagy. Some candidates include existing drugs approved for cardiovascular disease and other conditions, which may help speed up the approval process.

Autophagy can be induced by fasting. When cells run short on proteins from an individual’s diet, they fill the void by recycling proteins already present in cells. Exercise also increases autophagy. 

These measures, as well as drug therapies, may ultimately help prevent the disease. “If a slowdown in autophagy is the underlying cause, things that increase it should have the beneficial, opposite effect,” Julian said. 

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Scientists Discover New Cause of Vascular Dementia and Alzheimer’s

By Oregon Health & Science University December 13, 2023

Researchers have discovered a new aspect of Alzheimer’s and vascular dementia: ferroptosis-induced microglia cell death. This groundbreaking finding, highlighting the vulnerability of brain immune cells, opens new possibilities for dementia treatment and early intervention strategies.

The study highlights the degeneration of microglia in the brain caused by iron toxicity.

Scientists have identified a new avenue of cell death in Alzheimer’s disease and vascular dementia.

Recent research, led by scientists at Oregon Health & Science University and published in the journal Annals of Neurology , reveals for the first time that a form of cell death known as ferroptosis — caused by a buildup of iron in cells — destroys microglia cells, a type of cell involved in the brain’s immune response, in cases of Alzheimer’s and vascular dementia.

Methodology and Key Discoveries

The researchers conducted the study examining post-mortem human brain tissue of patients with dementia.

“This is a major finding,” said senior author Stephen Back, M.D., Ph.D., a neuroscientist and professor of pediatrics in the OHSU School of Medicine.

Back has long studied myelin, the insulation-like protective sheath covering nerve fibers in the brain, including delays in forming myelin in premature infants. The new research extends that line of work by uncovering a cascading form of neurodegeneration triggered by the deterioration of myelin. They made the discovery using a novel technique developed by the study’s lead author Philip Adeniyi, Ph.D., a postdoctoral researcher in Back’s laboratory.

The researchers discovered that microglia degenerates in the white matter of the brain of patients with Alzheimer’s and vascular dementia.

Microglia Degeneration and Its Implications

Microglia are resident cells in the brain normally involved in clearing cellular debris as part of the body’s immune system. When myelin is damaged, microglia swarm in to clear the debris. In the new study, researchers found that microglia themselves are destroyed by the act of clearing iron-rich myelin — a form of cell death known as ferroptosis.

Given the intense scientific focus on the underlying cause of dementia in older adults, Back called it amazing that researchers hadn’t made the connection to ferroptosis until now.

“We’ve missed a major form of cell death in Alzheimer’s disease and vascular dementia,” Back said. “We hadn’t been giving much attention to microglia as vulnerable cells, and white matter injury in the brain has received relatively little attention.”

Co-author Kiera Degener-O’Brien, M.D., initially discovered the degeneration of microglia in tissue samples, Back said. Adeniyi subsequently developed a novel immunofluorescence technique to determine that iron toxicity was causing microglial degeneration in the brain. This was likely a result of the fact that the fragments of myelin are themselves rich in iron, Back said.

In effect, the immune cells were dying in the line of duty.

“Everyone knows that microglia are activated to mediate inflammation,” Back said. “But no one knew that they were dying in such large numbers. It’s just amazing that we missed this until now.”

Potential Pharmaceutical Developments

The study finds that the cascading effect of degenerating microglia appears to be a mechanism in advancing cognitive decline in Alzheimer’s disease and vascular dementia, Back said. He expects pharmaceutical companies will use this new finding to develop compounds focused on reducing microglial degeneration in the brain.

“That’s where the field will go next,” he said. “A discovery like ours will stimulate a lot of excitement in the pharmaceutical industry to develop therapeutically important compounds.”

He said the underlying cause initiating the cycle of decline likely relates to repeated episodes of low blood flow and oxygen delivery to the brain over time due to acute stroke or chronic conditions such as hypertension and diabetes.

“Dementia is a process that goes on for years and years,” Back said. “We have to tackle this from the early days to have an impact so that it doesn’t spin out of control.”

Reference: “Ferroptosis of Microglia in Aging Human White Matter Injury” by Philip A. Adeniyi, Xi Gong, Ellie MacGregor, Kiera Degener-O’Brien, Evelyn McClendon, Mariel Garcia, Oscar Romero, Joshua Russell, Taasin Srivastava, Jeremy Miller, C. Dirk Keene and Stephen A. Back, 21 August 2023,  Annals of Neurology . DOI: 10.1002/ana.26770

The research was supported by grants from the National Institute on Aging (AG065406, AG031892, U01 AG006781, and U19 AG066567 which supports the ACT study, p50 AG005136 and p30AG066509, which support the UW Alzheimer’s disease Research Center) of the National Institutes of Health ; the National Institute of Neurological Disorders and Stroke of the NIH (NS105984); and by the Nancy and Buster Alvord Endowment. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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• Patient Care & Health Information
• Diseases & Conditions
• Alzheimer's disease

Alzheimer's disease is a brain disorder that gets worse over time. It's characterized by changes in the brain that lead to deposits of certain proteins. Alzheimer's disease causes the brain to shrink and brain cells to eventually die. Alzheimer's disease is the most common cause of dementia — a gradual decline in memory, thinking, behavior and social skills. These changes affect a person's ability to function.

About 6.5 million people in the United States age 65 and older live with Alzheimer's disease. Among them, more than 70% are 75 years old and older. Of the about 55 million people worldwide with dementia, 60% to 70% are estimated to have Alzheimer's disease.

The early signs of the disease include forgetting recent events or conversations. Over time, it progresses to serious memory problems and loss of the ability to perform everyday tasks.

Medicines may improve or slow the progression of symptoms. Programs and services can help support people with the disease and their caregivers.

There is no treatment that cures Alzheimer's disease. In advanced stages, severe loss of brain function can cause dehydration, malnutrition or infection. These complications can result in death.

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Memory loss is the key symptom of Alzheimer's disease. Early signs include difficulty remembering recent events or conversations. But memory gets worse and other symptoms develop as the disease progresses.

At first, someone with the disease may be aware of having trouble remembering things and thinking clearly. As symptoms get worse, a family member or friend may be more likely to notice the issues.

Brain changes associated with Alzheimer's disease lead to growing trouble with:

Everyone has memory lapses at times, but the memory loss associated with Alzheimer's disease persists and gets worse. Over time, memory loss affects the ability to function at work or at home.

People with Alzheimer's disease may:

• Repeat statements and questions over and over.
• Forget conversations, appointments or events.
• Misplace items, often putting them in places that don't make sense.
• Get lost in places they used to know well.
• Eventually forget the names of family members and everyday objects.
• Have trouble finding the right words for objects, expressing thoughts or taking part in conversations.

Thinking and reasoning

Alzheimer's disease causes difficulty concentrating and thinking, especially about abstract concepts such as numbers.

Doing more than one task at once is especially difficult. It may be challenging to manage finances, balance checkbooks and pay bills on time. Eventually, a person with Alzheimer's disease may be unable to recognize and deal with numbers.

Making judgments and decisions

Alzheimer's disease causes a decline in the ability to make sensible decisions and judgments in everyday situations. For example, a person may make poor choices in social settings or wear clothes for the wrong type of weather. It may become harder for someone to respond to everyday problems. For example, the person may not know how to handle food burning on the stove or decisions when driving.

Planning and performing familiar tasks

Routine activities that require completing steps in order become a struggle. This may include planning and cooking a meal or playing a favorite game. Eventually, people with advanced Alzheimer's disease forget how to do basic tasks such as dressing and bathing.

Changes in personality and behavior

Brain changes that occur in Alzheimer's disease can affect moods and behaviors. Problems may include the following:

• Depression.
• Loss of interest in activities.
• Social withdrawal.
• Mood swings.
• Distrust in others.
• Anger or aggression.
• Changes in sleeping habits.
• Loss of inhibitions.
• Delusions, such as believing something has been stolen.

Preserved skills

Despite major changes to memory and skills, people with Alzheimer's disease are able to hold on to some skills even as symptoms get worse. Preserved skills may include reading or listening to books, telling stories, sharing memories, singing, listening to music, dancing, drawing, or doing crafts.

These skills may be preserved longer because they're controlled by parts of the brain affected later in the course of the disease.

When to see a doctor

A number of conditions can result in memory loss or other dementia symptoms. Some of those conditions can be treated. If you are concerned about your memory or other thinking skills, talk to your health care professional.

If you are concerned about thinking skills you observe in a family member or friend, talk about your concerns and ask about going together to talk to a health care professional.

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• Healthy brain and brain with Alzheimer's disease

In the brain of someone with Alzheimer's disease, amyloid plaques form and tau proteins change shape and become tangles.

The exact causes of Alzheimer's disease aren't fully understood. But at a basic level, brain proteins fail to function as usual. This disrupts the work of brain cells, also called neurons, and triggers a series of events. The neurons become damaged and lose connections to each other. They eventually die.

Scientists believe that for most people, Alzheimer's disease is caused by a combination of genetic, lifestyle and environmental factors that affect the brain over time. In less than 1% of cases, Alzheimer's is caused by specific genetic changes that almost guarantee a person will develop the disease. In these cases, the disease usually begins in middle age.

The development of the disease begins years before the first symptoms. The damage most often starts in the region of the brain that controls memory. The loss of neurons spreads in a somewhat predictable pattern to other regions of the brain. By the late stage of the disease, the brain has shrunk significantly.

Researchers trying to understand the cause of Alzheimer's disease are focused on the role of two proteins:

• Plaques. Beta-amyloid is a fragment of a larger protein. When these fragments clump together, they appear to have a toxic effect on neurons and to disrupt communication between brain cells. These clumps form larger deposits called amyloid plaques, which also include other cellular debris.
• Tangles. Tau proteins play a part in a brain cell's internal support and transport system to carry nutrients and other essential materials. In Alzheimer's disease, tau proteins change shape and organize into structures called neurofibrillary tangles. The tangles disrupt the transport system and cause damage to cells.
• Mayo Clinic Minute: Women and Alzheimer's Disease

Risk factors

Increasing age is the greatest known risk factor for Alzheimer's disease. Alzheimer's isn't a part of typical aging. But as you grow older, the chances of developing it increases.

One study found that every year there were four new diagnoses per 1,000 people ages 65 to 74. Among people ages 75 to 84, there were 32 new diagnoses per 1,000 people. For those 85 and older, there were 76 new diagnoses per 1,000 people.

Family history and genetics

The risk of developing Alzheimer's is somewhat higher if a first-degree relative — your parent or sibling — has the disease. Just how genes among families affect the risk is largely unexplained, and the genetic factors are likely complex.

A better understood genetic factor is a form of the apolipoprotein E ( APOE ) gene. A form of the gene, APOE e4 , increases the risk of Alzheimer's disease. About 25% to 30% of the population carries APOE e4 . But not everyone with this form of the gene develops the disease.

Scientists have found rare changes in three genes that virtually guarantee a person who inherits one of them will develop Alzheimer's. But these changes account for less than 1% of people with Alzheimer's disease.

Down syndrome

Many people with Down syndrome develop Alzheimer's disease. This is likely related to having three copies of chromosome 21. Chromosome 21 is the gene involved in the production of the protein that leads to the creation of beta-amyloid. Beta-amyloid fragments can become plaques in the brain. Symptoms tend to appear 10 to 20 years earlier in people with Down syndrome than they do for the general population.

Overall there are more women with the disease because they tend to live longer than men.

Mild cognitive impairment

Someone with mild cognitive impairment (MCI) has a decline in memory or other thinking skills that is greater than usual for the person's age. But the decline doesn't prevent the person from functioning in social or work environments.

However, people with MCI have a significant risk of developing dementia. When MCI affects mainly memory, the condition is more likely to progress to dementia due to Alzheimer's disease. A diagnosis of MCI offers people the chance to put a greater focus on healthy lifestyle changes and to come up with strategies to make up for memory loss. They also can schedule regular health care appointments to monitor symptoms.

Head trauma

Several large studies found that people age 50 years or older who had a traumatic brain injury (TBI) had an increased risk of dementia and Alzheimer's disease. The risk is even higher in people with more-severe and multiple TBIs . Some studies found that the risk may be greatest within the first six months to two years after the injury.

Air pollution

Studies in animals have found that air pollution particulates can speed the breakdown of the nervous system. And human studies have found that air pollution exposure — especially from traffic exhaust and burning wood — is linked to a greater dementia risk.

Excessive alcohol consumption

Drinking large amounts of alcohol has long been known to cause brain changes. Several large studies and reviews found that alcohol use disorders were linked to an increased risk of dementia — early-onset dementia in particular.

Poor sleep patterns

Research has shown that poor sleep patterns, such as trouble falling asleep or staying asleep, are linked to an increased risk of Alzheimer's disease.

Lifestyle and heart health

Research has shown that the same risk factors associated with heart disease also may increase the risk of dementia. It's unclear if these factors increase risk of dementia by worsening Alzheimer's changes in the brain or by leading to brain vascular changes. They include:

• Lack of exercise.
• Smoking or exposure to secondhand smoke.
• High blood pressure.
• High cholesterol.
• Poorly controlled type 2 diabetes.

These factors can all be modified. Therefore, changing lifestyle habits can to some degree alter your risk. For example, regular exercise and a healthy low-fat diet rich in fruits and vegetables are related to a lower risk of Alzheimer's disease.

Lifelong learning and social engagement

Studies have found that socializing and engaging in activities that stimulate the mind throughout life can lower the risk of Alzheimer's disease. Low education levels — less than a high school education — appear to be a risk factor for Alzheimer's disease.

Complications

Alzheimer's symptoms such as memory loss, language loss, impaired judgment and other brain changes can make it harder to manage other health conditions. A person with Alzheimer's disease may not be able to:

• Tell someone about being in pain.
• Explain symptoms of another illness.
• Follow a treatment plan.
• Explain medicine side effects.

As Alzheimer's disease moves into its last stages, brain changes begin to affect physical functions. The changes can affect the ability to swallow, balance, and control bowel and bladder movements. These effects can lead to other health problems such as:

• Inhaling food or liquid into the lungs.
• Flu, pneumonia and other infections.
• Poor nutrition or dehydration.
• Constipation or diarrhea.
• Dental problems such as mouth sores or tooth decay.

Alzheimer's disease is not a preventable condition. However, a number of lifestyle risk factors can be modified.

Evidence suggests that taking steps to reduce the risk of cardiovascular disease may also lower your risk of developing dementia.

To follow heart-healthy lifestyle choices that may reduce the risk of dementia:

• Exercise regularly.
• Eat a diet of fresh produce, healthy oils and foods low in saturated fat, such as a Mediterranean diet.
• Follow treatment guidelines to manage high blood pressure, diabetes and high cholesterol.
• If you smoke, ask your health care professional for help to quit.

One large, long-term study done in Finland found that making lifestyle changes helped reduce cognitive decline among people who were at risk of dementia. Those in the study were given individual and group sessions that focused on diet, exercise and social activities.

In another study done in Australia, people at risk of dementia were given coaching sessions on diet, exercise and other lifestyle changes. They had better results on cognitive tests after one, two and three years compared to people who didn't receive the coaching.

Other studies have shown that staying engaged mentally and socially is linked to preserved thinking skills later in life and a lower risk of Alzheimer's disease. This includes going to social events, reading, dancing, playing board games, creating art, playing an instrument and other activities.

• Alzheimer's prevention: Does it exist?
• Jankovic J, et al., eds. Alzheimer disease and other dementias. In: Bradley and Daroff's Neurology in Clinical Practice. 8th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed Sept. 21, 2022.
• Alzheimer's disease fact sheet. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet. Accessed Oct. 3, 2022.
• Livingston G, et al. Dementia prevention, intervention, and care: 2020 report of The Lancet Commission. The Lancet. 2020; doi:10.1016/S0140-6736(20)30367-6.
• Chen L, et al. Plasma tau proteins for the diagnosis of mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis. Frontiers in Aging Neuroscience. 2022; doi:10.3389/fnagi.2022.942629.
• Dementia. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/dementia. Accessed Oct. 3, 2022.
• Alzheimer's disease and related dementias. Centers for Disease Control and Prevention. https://www.cdc.gov/aging/aginginfo/alzheimers.htm. Accessed Oct. 3, 2022.
• What is dementia? Symptoms, types, and diagnosis. National Institute on Aging. https://www.nia.nih.gov/health/diagnosing-dementia. Accessed Oct. 3, 2022.
• Biomarkers for dementia detection and research. National Institute on Aging. https://www.nia.nih.gov/health/biomarkers-dementia-detection-and-research. Accessed Oct. 3, 2022.
• Middle-stage caregiving. Alzheimer's Association. https://www.alz.org/help-support/caregiving/stages-behaviors/middle-stage. Accessed Oct. 3, 2022.
• Kellerman RD, et al. Alzheimer's disease. In: Conn's Current Therapy 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed Sept. 21, 2022.
• Ferri FF. Alzheimer disease. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Oct. 3, 2022.
• Early-stage caregiving. Alzheimer's Association. https://www.alz.org/help-support/caregiving/stages-behaviors/early-stage. Accessed Oct. 3, 2022.
• Alzheimer's disease at a glance. National Center for Complementary and Integrative Health. https://nccih.nih.gov/health/alzheimer/ataglance. Accessed Oct. 3, 2022.
• Budson AE, et al. Alzheimer's disease. In: Memory Loss, Alzheimer's Disease, and Dementia. 3rd ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed Oct. 3, 2022.
• Coping with late-stage Alzheimer's disease. National Institute on Aging. https://www.nia.nih.gov/health/coping-late-stage-alzheimers-disease. Accessed Oct. 3, 2022.
• Levenson JL, ed. Dementia. In: The American Psychiatric Association Publishing Textbook of Psychosomatic Medicine and Consultation-Liaison Psychiatry. 3rd ed. American Psychiatric Association Publishing; 2019. https://psychiatryonline.org. Accessed Oct. 3, 2022.
• Dementia: Lifestyle and management. American Geriatrics Society. https://www.healthinaging.org/a-z-topic/dementia/lifestyle. Accessed Oct. 5, 2022.
• Is Alzheimer's genetic? Alzheimer's Association. https://www.alz.org/alzheimers-dementia/what-is-alzheimers/causes-and-risk-factors/genetics. Accessed Oct. 6, 2022.
• Ami T. Allscripts EPSi. Mayo Clinic. July 6, 2022.
• Alzheimer's disease research centers. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-disease-research-centers#minnesota. Accessed Sept. 26, 2022.
• About the Alzheimer's Consortium. Arizona Alzheimer's Consortium. https://azalz.org/about/#institutes. Accessed Sept. 26, 2022.
• Graff-Radford J (expert opinion). Mayo Clinic. Oct. 6, 2022.
• 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.
• Cummings J, et al. Alzheimer's disease drug development pipeline: 2022. Alzheimer's and Dementia. 2022; doi:10.1002/trc2.12295.
• Leqembi (prescribing information). Eisai Inc.; 2023. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=761269. Accessed July 10, 2023.
• Mintun MA, et al. Donanemab in early Alzheimer's disease. New England Journal of Medicine. 2021; doi:10.1056/NEJMoa2100708.
• 2022 Alzheimer's disease facts and figures. Alzheimer's Association. https://www.alz.org/alzheimers-dementia/facts-figures. Accessed Oct. 4, 2022.
• Rosenberg A, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer's disease and dementia: From FINGER to world-wide FINGERS. The Journal of Prevention of Alzheimer's Disease. 2020; doi:10.14283/jpad.2019.41.
• Bleicher K, et al. Cohort profile update: The 45 and up study. International Journal of Epidemiology. 2022; doi:10.1093/ije/dyac104.
• 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.
• Swaddiwudhipong N, et al. Pre-diagnostic cognitive and functional impairment in multiple sporadic neurodegenerative diseases. Alzheimer's and Dementia. 2022; doi:10.1002/alz.12802.
• Van Dyck CH, et al. Lecanemab in early Alzheimer's disease. New England Journal of Medicine. 2023; doi:10.1056/NEJMoa2212948.
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Thousands to be offered blood tests for dementia in UK trial

More than 50 clinics will offer tests to about 5,000 people who are worried about their memory in five-year trial

Thousands of people across the UK who are worried about their memory will receive blood tests for dementia in two trials that doctors hope will help to revolutionise the low diagnosis rate.

Teams from the University of Oxford and University College London will lead the trials to research the use of cheap and simple tests to detect proteins for people with early stages of dementia or problems with cognition, with the hope of speeding up diagnosis and reaching more people.

Currently, getting a formal diagnosis in the UK relies on mental ability tests, brain scans or invasive and painful lumbar punctures, where a sample of cerebrospinal fluid is drawn from the lower back.

About 1 million people are living with the condition in Britain, and this is expected to rise to about 1.7 million by 2040 – with potentially grim consequences. In 2022, dementia took the lives of 66,000 people in England and Wales, and it is now the leading cause of death in Britain, with Alzheimer’s accounting for two-thirds of cases.

Patients and their families have been reported to wait for up to four years to get an appointment and the results, according to charities. More than one in three people living with dementia in England are yet to receive a formal diagnosis.

The tests are highly effective in research settings, so if they prove as useful in real life, they could make the diagnosis of Alzheimer’s more accessible.

They could provide results to patients much sooner and accelerate the introduction of new Alzheimer’s drugs that rely on early diagnosis. The trial will help determine if they can be rolled out routinely on the NHS.

Fiona Carragher, the director of research and influencing at the Alzheimer’s Society, said the reliance on specialised tests had led to “unnecessary delays, worry and uncertainty” that meant people often could not access the care they needed early on.

“Dementia is the UK’s biggest killer, yet a third of people living with dementia don’t have a diagnosis, which means they’re not able to access care and support. At the moment, only 2% of people with dementia can access the specialised tests needed to demonstrate eligibility for new treatments, leading to unnecessary delays, worry and uncertainty,” she said.

The research teams are sponsored by Alzheimer’s Research UK and the Alzheimer’s Society, with £5m of funding from the People’s Postcode Lottery.

Dr Sheona Scales, the 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. Now we need to see this same step change in dementia, which is the greatest health challenge facing the UK.

“It’s fantastic that through collaborating with the leading experts in the dementia community, we can look to bring cutting-edge blood tests for diagnosing dementia within the NHS. And this will be key to widening access to groundbreaking new treatments that are on the horizon.”

More than 50 memory clinics across the UK will be offering blood tests to about 5,000 volunteers as part of the five-year trial.

Jonathan Schott, the chief medical officer at Alzheimer’s Research UK, will lead a trial on the most promising blood biomarker in tests on 1,100 people across the UK.

The second trial will test for multiple forms of dementia, including Alzheimer’s disease, vascular dementia, frontotemporal dementia and dementia with Lewy bodies on about 4,000 people.

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Blood test could revolutionise diagnosis of Alzheimer’s, experts say

Alcohol misuse and loneliness ‘increase risk of early-onset dementia’

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Healthy blood flow to brain could help stave off dementia, study says

Scientists have uncovered a potential new route to developing drug treatments for the second most common type of dementia .

New research has shed light on to how high blood pressure causes changes to arteries in the brain, a process that restricts blood flow to the organ, resulting in vascular dementia.

Scientists hope the discovery will accelerate the development of treatments for the condition, which affects around 150,000 people in the UK .

“By uncovering how high blood pressure causes arteries in the brain to remain constricted, our research reveals a new avenue for drug discovery that may help to find the first treatment for vascular dementia,” Professor Adam Greenstein, a clinician scientist specialising in high blood pressure at the University of Manchester, and one of the leaders of the research, said.

“Allowing blood to return as normal to damaged areas of the brain will be crucial to stopping this devastating condition in its tracks.

“Any drugs that are discovered to improve brain blood supply may also be able to open a new line of attack in treating Alzheimer’s disease, which causes very similar damage to blood vessels as vascular dementia.

“Drugs to restore healthy blood flow could make current treatments, which focus on removing harmful amyloid plaques in the brain, more effective.”

High blood pressure is a main cause of vascular dementia, a condition characterised by poor blood flow to the brain.

The reduced blood supply starves brain cells of nutrients and over time they become damaged and die.

Symptoms of the condition include loss of energy, lack of concentration and poor memory.

Five best foods to eat for memory, concentration and overall brain health – in pictures

While it is normal for the brain’s arteries to narrow and widen in response to changes in blood pressure, consistently high blood pressure causes arteries to stay narrow and restrict the brain’s blood supply.

However, until now, it was not known how this happened.

The study, from researchers at the Geoffrey Jefferson Brain Research Centre at The University of Manchester, reveals that – in mice – high blood pressure disrupts messaging within artery cells in the brain.

This occurs when two cell structures that normally help to transmit messages that tell arteries to dilate, move further apart.

According to the findings, this stops the messages reaching their target, which causes the arteries to remain permanently constricted, limiting blood flow to the brain.

The experts hope that by identifying drugs that could restore this communication, it may soon be possible to improve blood supply to affected areas of the brain and slow the progression of vascular dementia.

While the findings are yet to be confirmed in humans, the processes of blood vessel narrowing and widening are very similar in mice and humans.

The study was funded by the British Heart Foundation (BHF) and published in the journal Proceedings of the National Academy of Sciences .

“Vascular dementia affects around 150,000 people in the UK, and this number is going up,” Professor Sir Nilesh Samani, medical director at the BHF, said.

“There are no treatments to slow or stop the disease, but we know that high blood pressure is an important risk factor. The incurable symptoms are hugely distressing for patients and those close to them.

“This exciting research reveals a specific mechanism by which high blood pressure might increase the risk of vascular dementia.

“Pinpointing how arteries remain permanently narrowed in vascular dementia could lead to the development of new effective treatments, raising hope that there may soon be a way to prevent this illness from destroying more lives.”

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How to Reverse Insulin Resistance

A q&a with gerald shulman, gerald i. shulman, md, phd.

Gerald I. Shulman, MD, PhD , George R. Cowgill Professor of Medicine (Endocrinology) and Cellular and Molecular Physiology, Investigator Emeritus of the Howard Hughes Medical Institute, and co-director of the Yale Diabetes Research Center, studies the molecular basis for insulin resistance, a condition found in approximately forty percent of U.S. adults.

“One of the major threats to global health in the 21st century, insulin resistance is a key factor in the development of type 2 diabetes, cardiovascular disease, fatty liver disease, neurogenerative disease, and obesity-associated cancers,” Shulman said. “Understanding the molecular basis for insulin resistance can lead to novel therapies that help prevent these diseases.”

Shulman is the recipient of numerous awards, including the American Diabetes Association’s Banting Medal for Scientific Achievement, the European Association for the Study of Diabetes-Lilly Centennial Anniversary Prize, the American Society of Clinical Investigation’s Stanley J. Korsmeyer Award, and the Endocrine Society’s Outstanding Clinical Investigator Award. Most recently, he was selected for the Bodil M. Schmidt-Nielsen Distinguished Mentor and Scientist Award, which recognizes a member of the American Physiological Society who has made outstanding contributions to research and to training the next generation of physiologists.

In a Q&A, Shulman discusses the basics of insulin resistance, how the condition impacts our health, and the steps we can take to reverse it.

What is insulin resistance?

The hormone insulin, which is produced by the pancreas, regulates blood glucose, or sugar from the food we eat, by allowing it to enter the body’s cells, where it is used for energy. Insulin resistance—found in both lean and overweight individuals—is when the body’s cells don’t effectively respond to insulin and take in glucose, leading to high blood sugar levels.

What causes it?

My lab has found that insulin resistance in liver and skeletal muscle, the organs where insulin normally promotes glucose storage as glycogen, is linked to increased ectopic lipid accumulation, or fat accumulation inside the liver and muscle cells.

Why has evolution preserved insulin resistance, something we think of as a deleterious process? It turns out insulin resistance is activated during starvation. During starvation, your body breaks down stored lipid in the white adipose tissue, which becomes mobilized and leads to fat accumulation in liver and muscle cells. These organs become insulin-resistant, which in turn preserves glucose in the bloodstream to fuel brain metabolism and other obligatory glucose-requiring cells in the body (e.g., red blood cells). In this way, insulin resistance is a normal physiological process that has promoted survival from starvation in mammals throughout evolution.

But now, insulin resistance is activated by overnutrition in our toxic food environment.

How does being insulin-resistant impact our health?

Insulin resistance is the major reason people go on to develop type 2 diabetes. The condition also results in metabolic dysfunction-associated steatotic liver disease, in which the body stores excess fat in the liver, and steatohepatitis, which can progress to end-stage liver disease and liver cancer. Muscle insulin resistance also leads to increased plasma triglycerides and LDL, the bad cholesterol, which are major contributors to heart disease.

Insulin resistance is also associated with obesity-related cancers. When you’re insulin resistant, your pancreas produces more insulin, which promotes tissue growth. In preclinical studies, my collaborators and I have shown that insulin resistance promotes the growth of breast and colon cancers.

Finally, insulin resistance is likely a major driver of Alzheimer’s disease.

How can we reduce or reverse insulin resistance?

Our research has shown that modest weight reduction due to caloric restriction to about 1,200 calories a day leads to a reduction of liver fat and reversal of liver insulin resistance and type 2 diabetes. You don’t have to get down to the weight you were in high school—a 10% weight reduction can make a big difference. This is also likely the major mechanism by which the new GLP-1 agonist medications are working to reverse type 2 diabetes.

We have also learned that exercise opens the door for glucose transport into the muscle cell, bypassing the block in insulin action. If you have muscle insulin resistance, you can normalize the storage of ingested carbohydrate into the muscle as glycogen, decreasing the conversion of carbohydrate to fat in the liver. This, in turn, leads to protection from the development of fatty liver disease and improvement in the plasma lipid profile, which will protect against the development of atherosclerosis.

I encourage my patients with diabetes or prediabetes to find a physical activity they like to do every day and stick with it.

As we deepen our understanding of the molecular basis of insulin resistance and develop new drugs to target this mechanism, I’m optimistic about the future of treating insulin resistance and improving cardiometabolic health.

Yale School of Medicine’s Section of Endocrinology and Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge, applying new information to patient care, and training the next generation of physicians and scientists to become leaders in the field. To learn more, visit Endocrinology & Metabolism .

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April 9, 2024

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Researchers call for focus on higher stroke risk in women

by Medical University of South Carolina

While stroke is the fifth-leading cause of death for men, it's the third-leading cause of death for women in the United States.

Someone's risk of stroke increases as they age, and since women continue to live longer than men, they have more strokes over their lifetimes. However, a review article in the Journal of Stroke and Cerebrovascular Diseases has found that the risk is more complex than what can be explained only by an increased lifespan.

Parneet Grewal, M.D., is an assistant professor of vascular neurology at MUSC and the senior author on the paper. She says the differences in stroke rates are concerning and should be considered a massive public health concern. "It's paramount that we understand these gaps in knowledge and develop targeted approaches in reducing mortality and morbidity from stroke," Grewal said.

There are two types of stroke: ischemic stroke and hemorrhagic stroke . According to the National Heart, Lung and Blood Institute, the former occurs when blood clots or other particles block the blood vessels to the brain, restricting oxygen and nutrients. The latter refers to a sudden leaking or burst in a blood vessel, which can increase brain pressure.

After reviewing the published literature, Grewal and her team saw different trends in both traditional and nontraditional stroke risk factors between men and women. Hypertension, obesity, diabetes, hyperlipidemia and smoking are well-established risks for stroke in both men and women, but as they age, women have an increased risk of stroke related to some of these disorders.

Women appear to be more sensitive to high blood pressure than men. As the most prevalent modifiable risk factor for stroke, high blood pressure is something patients can potentially control with lifestyle changes. A large national study from 2019 found that the association between increasing blood pressure severity and risk of ischemic stroke was double in women when compared to men.

Other factors—like late puberty, early menopause, pregnancy and its complications and hormonal therapy—can significantly affect a woman's risk as well. Grewal focused on disorders of pregnancy that result in high blood pressure since women who develop these disorders are overall at an increased risk of mortality and stroke. She says she has also seen long-term effects later in life for these women and that the current tool for predicting risk likely underestimates the risk for cardiovascular disease in women who had high blood pressure during pregnancy.

Grewal stressed adequate education and follow-up appointments, as well as early detection and treatment, for improved outcomes for these women.

Grewal hopes that by applying this knowledge to patient care and education as well as developing targeted risk reduction strategies, women could see a more tailored approach to their stroke prevention in the future.

In their review, MUSC's research team was not focused on the causes of stroke or stroke outcomes, but on the trends in risk factors. Grewal hopes to dive into that side of the research next. More research on nontraditional causes of stroke may help researchers develop further prevention methods.

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