Research on Alzheimer's Disease

 

To consolidate memories, our brains replay them during periods of rest as a kind of 'replay mode'. A new mouse study suggests that disruptions to this process could contribute to the memory loss that accompanies Alzheimer's disease. According to the research team from University College London, these findings could lead the way towards opportunities to diagnose Alzheimer's at an earlier stage and to treat the associated brain damage.   

"Alzheimer's disease is caused by the build-up of harmful proteins and plaques in the brain, leading to symptoms such as memory loss and impaired navigation – but it's not well understood exactly how these plaques disrupt normal brain processes," says neuroscientist Sarah Shipley. "We wanted to understand how the function of brain cells changes as the disease develops, to identify what's driving these symptoms."  

The mice in the study were given an Alzheimer's-like condition, with toxic build-ups of amyloid-beta protein in their brains. When navigating mazes, the test animals showed signs of being unable to lock a spatial map into their memories. Both during the maze challenges and while the mice were at rest between sessions, Shipley and her colleagues monitored activity in their hippocampi, a region of the brain containing location-memory neurons known as place cells.  Brain replays were scrambled in Alzheimer's mice, who also performed worse on maze tasks. (Shipley et al., Curr. Biol., 2026)

For the mice to recall where they've been, these cells must fire in a particular order. As the memories are 'saved' for longer-term storage, that sequence of activation repeats, like a replay. The frequency of these replays didn't change in mice with amyloid-beta plaques in their brains, but the ordering of the sequences did. It was as if the memories were scenes in a mini movie, which were chopped up and stored in different places.

This was seen in maze behavior, too, with the affected mice often forgetting which parts of the maze they had already visited, even in the same session. The place cells also became less stable over time, with the cell-to-location mapping becoming messed up. 

Although this study used a model of Alzheimer's in mouse brains, there are good reasons to think the same kind of breakdown is happening in humans with the disease – something that could be confirmed through future studies. "We've uncovered a breakdown in how the brain consolidates memories, visible at the level of individual neurons," says neuroscientist Caswell Barry. "What's striking is that replay events still occur – but they've lost their normal structure. It's not that the brain stops trying to consolidate memories; the process itself has gone wrong."

Alzheimer's disease is a complex condition with multiple risk factors. There are various potential causes and numerous impacts on the brain, which may be working together or separately. Part of the difficulty for researchers comes in trying to work out what's driving the progress of Alzheimer's, and what's happening as a consequence of it – and there's that uncertainty around amyloid-beta build-up too.

Studies like this add pieces to the overall jigsaw, letting us see more of the 'big picture' of Alzheimer's – and how all these causes and consequences fit together as brain functionality degrades over time. Each new discovery means that we might be able to spot signs of the disease earlier – giving more time for treatments and support to be put in place – and develop treatments to target certain parts of Alzheimer's. In this case, that might be drugs that help to sharpen replay activity in the hippocampus's place cells. 

However, that won't be possible until more research can specifically identify the processes at play and how they can be safely tweaked.  "We hope our findings could help develop tests to detect Alzheimer's early, before extensive damage has occurred, or lead to new treatments targeting this replay process," says Barry.

The research has been published in Current Biology.    

  

Green Tea and a Vitamin Supplement Could Protect against Alzheimer's

 

A natural compound found in green tea forms a powerful brain cleaner when combined with a common vitamin, researchers have found, potentially putting the brakes on the buildup of waste associated with diseases such as Alzheimer's.   

What makes the discovery particularly exciting is that these substances can be attained through a healthy diet and are widely available as dietary supplements that have been cleared as safe by regulators.

The findings are the result of a study by researchers at the University of California Irvine (UC Irvine) on the antioxidant epigallocatechin gallate  and The findings are the nicotinamide, a type of vitamin B3 that's made naturally in the body from niacin-rich foods such as cereals, fish, nuts, legumes, and eggs.

"By supplementing the brain's energy systems with compounds that are already available as dietary supplements, we may have a new path toward treating age-related cognitive decline and Alzheimer's disease," says biomedical engineer Gregory Brewer.

In tests on lab-cultured mouse neurons, epigallocatechin gallate and nicotinamide were shown to boost the energy molecule guanosine triphosphate (GTP), found in brain cells. GTP provides essential energy for cleaning up dead cells, with a lack of the compound previously being linked to the development of Alzheimer's in aging brains.

GTP-boosted neurons were shown to help the brain clear out damaging clumps of amyloid beta proteins, which have long been linked with the progression of Alzheimer's. The compounds also reversed damage associated with age in brain cells.

While GTP has previously been linked with neurodegeneration, the study reveals how levels can drop over time, especially when Alzheimer's is involved. 

The researchers speculate that the combination of epigallocatechin gallate and nicotinamide may return GTP to levels found in younger cells. "This study highlights GTP as a previously underappreciated energy source driving vital brain functions," says Brewer.

Earlier this year, a separate study linked green tea with fewer white matter lesions in the brain, and in turn a lower dementia risk, though the research didn't prove direct cause and effect. Nicotinamide has also been implicated in protecting neurons from the effects of stroke and neurodegeneration.

Thanks to this research, we know that GTP might be part of the reason why – and that epigallocatechin gallate and nicotinamide could make a critical difference together. It's going to take some time to turn this into a treatment, and it's important to note that this has only been tested in mouse cells in vitro, but the results are encouraging. "As people age, their brains show a decline in neuronal energy levels, which limits the ability to remove unwanted proteins and damaged components," says Brewer.

-David Nield, Science Alert, NewsBreak

Can Lithium be used to treat Alzheimer's disease?

Lithium deficiency in the brain could be a cause of Alzheimer's disease—and a new potential target for treatment. Ten years in the making, this is the finding of researchers at Harvard Medical School who have revealed how lithium plays an essential role in brain function and may provide resistance against brain aging and Alzheimer's.

Lithium is a chemical element, currently used as medicine to treat mood disorders like mania and bipolar disorder. "Most people associate lithium with psychiatric treatment. Our study shows, for the first time, that naturally occurring lithium plays a crucial role in maintaining brain health during aging—even at concentrations far below those used in clinical psychiatry," study authors Bruce Yankner and Liviu Aron told Newsweek.

The findings are based on a series of experiments in mice and on analyses of human brain tissue and blood samples from individuals in various stages of cognitive health. "We found that lithium is uniquely depleted in the brains of people with mild cognitive impairment—a precursor to Alzheimer's. This makes lithium deficiency one of the earliest biochemical signs of the disease, possibly years before clinical symptoms appear," the duo explained.

"We also saw that higher endogenous lithium levels were associated with preserved cognitive function even in individuals without Alzheimer's. So, this isn't just about preventing disease—it's about supporting healthy brain aging in general."

The new revelation helps to explain why some people with Alzheimer's-like abnormalities in the brain don't go on to develop the disease. While genetic and environmental factors play a role, scientists also haven't been able to suggest why some people with the same risk factors might develop it and others don't—until now.

The scientists unearthed that lithium loss in the human brain is one of the earliest changes leading to Alzheimer's. In mice, meanwhile, similar lithium depletion accelerated brain pathology (disease or abnormality) and memory decline.

They also found reduced lithium levels stemmed from binding to amyloid plaques (misfolded proteins found between nerve cells found in the brains of people with Alzheimer's) and impaired uptake in the brain.

In their final set of experiments, they found a new lithium compound that avoids "capture" by amyloid plaques restored memory in mice. "In people that start experiencing memory loss, the so-called mild cognitive impairment, lithium gets trapped by amyloid plaques—reducing its availability just when it's most needed to protect against inflammation and neurodegeneration," Yankner and Aron explained. "This creates a self-perpetuating feedback loop of worsening pathology and accelerating disease progression and memory loss."

This all ties together decades-long observations in patients and provides a new theory of the disease and strategy for early diagnosis, prevention and treatment, according to the researchers.

Recently developed treatments that target amyloid beta (a key component of the amyloid plaques) typically don't reverse memory loss and only modestly reduce the rate of decline. "The idea that lithium deficiency could be a cause of Alzheimer's disease is new and suggests a different therapeutic approach," said Yankner in a statement.

Researchers had previously found lithium to be the only metal that had markedly different levels across people with and without Alzheimer's at different stages. But Yankner added in a statement, "Lithium turns out to be like other nutrients we get from the environment, such as iron and vitamin C. It's the first time anyone's shown that lithium exists at a natural level that's biologically meaningful without giving it as a drug." 

Previous population studies have shown that higher lithium levels in the environment, including in drinking water, tracked with lower rates of dementia. Yankner's team demonstrated in mice that lithium depletion isn't just linked to Alzheimer's, it actually helps drive it.

This raises hope that one day lithium could be used to treat the disease in its entirety rather than focusing on a single factor like amyloid beta or tau (another Alzheimer's-associated protein), Yankner said.

Crucially, the researchers discovered that as amyloid beta begins to form deposits in the early stages of dementia in both humans and mouse models, it binds to lithium, reducing lithium's function in the brain. The reduced levels of lithium affect all major brain cell types and, in mice, lead to changes similar to those seen in Alzheimer's disease, including memory loss.

Treating mice with the most potent amyloid-evading compound, called lithium orotate, reversed Alzheimer's pathology, prevented brain cell damage and restored memory.

While the findings need to be confirmed in humans through clinical trials, they suggest that measuring lithium levels could help screen for early Alzheimer's. They also highlight the importance of testing amyloid-evading lithium compounds for treatment or prevention.

While other lithium compounds are already used to treat bipolar disorder and clinical depression, they are given at much higher concentrations that can be toxic to some people, the researchers flag. Yankner's team discovered lithium orotate is effective at one-thousandth that dose— enough to mimic the natural level of lithium in the brain. Mice treated for nearly their entire adult lives showed no evidence of toxicity, the study found.

If further studies confirm these findings, the researchers say lithium screening through routine blood tests may one day offer a way to identify individuals at risk for Alzheimer's who would benefit from treatment to prevent or delay disease onset.

"Our study adds to growing evidence that Alzheimer's may be preventable—with something as simple as keeping brain lithium at healthy levels as we age," said Yankner and Aron.

"Clinical trials [on humans] could test the impact of low-dose supplementation on cognitive health and dementia risk."

Before lithium is proved to be safe and effective in protecting against neurodegeneration in humans, Yankner emphasized that people should not take lithium compounds on their own.

References

Aron, L., Ngian, Z. K., Qiu, C., Choi, J., Liang, M., Drake, D. M., Hamplova, S. E., Lacey, E. K., Roche, P., Yuan, M., Hazaveh, S. S., Lee, E. A., Bennett, D. A., & Yankner, B. A. (2025). Lithium deficiency and the onset of Alzheimer's disease. Nature. https://doi.org/10.1038/s41586-025-09335-x

-Hanna Millington, Newsweek

Surprising Alzheimer’s breakthrough: Sugar in neurons might be the missing link

 

A new study has identified an unexpected contributor to Alzheimer’s disease: glycogen, a complex sugar stored inside brain cells. While traditionally associated with muscles and the liver, glycogen appears to accumulate abnormally in neurons affected by Alzheimer’s and other tau-related disorders.

Scientists found that this buildup may worsen neurodegeneration by disrupting how cells manage energy and oxidative stress. Their findings, published in Nature Metabolism, suggest that breaking down glycogen could help protect neurons and offer a promising new direction for treating or preventing dementia.

Alzheimer’s disease is a progressive neurological condition that impairs memory, thinking, and behavior. It is the most common cause of dementia, especially among older adults. The disease is marked by two key biological abnormalities in the brain: plaques made of amyloid-beta protein and tangles made of another protein called tau.

These protein accumulations disrupt normal cell function, leading to inflammation, cell death, and brain shrinkage over time.

Despite extensive research, effective treatments for Alzheimer’s remain elusive. Most drug development has focused on clearing amyloid or tau from the brain, with limited success. Many researchers now believe that other factors, such as energy metabolism, inflammation, and oxidative stress, may play a role in determining who develops the disease and how quickly it progresses.

“Alzheimer’s disease, first identified over a century ago, remains one of the most challenging neurodegenerative conditions. Despite decades of research and numerous clinical trials aimed at targeting these aggregates, success has been limited,” said study author Pankaj Kapahi, a professor at the Buck Institute for Research on Aging.

“Surprisingly, many people with these protein buildups show little or no cognitive decline, and not everyone with hereditary risk factors develops the disease. This has led scientists to suspect that other overlooked factors may contribute to the onset and progression of Alzheimer’s.”

“Recent research has started to shine a light on the role of environmental and lifestyle factors—particularly diet—in shaping brain health. That question sparked our curiosity: could a rich diet influence the development of Alzheimer’s?”

Glycogen is the storage form of glucose, a sugar that serves as a vital source of energy. The liver and muscles contain most of the body’s glycogen, which is broken down when energy demands increase. The brain, though highly energy-dependent, contains only small amounts of glycogen, mainly in support cells called astrocytes. Neurons—the primary information-processing cells of the brain—have long been thought to store very little glycogen and to rely mainly on a continuous glucose supply from the bloodstream.

However, recent studies have hinted that neurons might store more glycogen than previously thought, especially in disease states. The Buck Institute researchers were interested in whether abnormal glycogen metabolism might be a hidden driver of Alzheimer’s and related tauopathies, and whether correcting it could slow or prevent the disease.

The research team used both fruit fly models and human stem cell-derived neurons to study tauopathies—diseases characterized by tau protein accumulation. In the fly experiments, they used genetic tools to overexpress human tau protein, including a mutant version linked to frontotemporal dementia. These flies developed signs of neurodegeneration, such as shortened lifespan, brain cell death, and structural damage.

The researchers compared flies fed a normal, protein-rich diet to those fed a low-protein, calorie-restricted diet, known to extend lifespan in many species. They also tested the effects of drugs and genetic changes that promote glycogen breakdown.

In parallel, they studied neurons derived from human induced pluripotent stem cells (iPSCs), including cells with two different tau mutations associated with dementia. These human neurons were grown in the lab and analyzed using fluorescent markers to assess glycogen accumulation, oxidative stress, and related metabolic activity.

The researchers found that tau-expressing neurons—both in flies and in human-derived cells—accumulated large amounts of glycogen. This buildup appeared to be linked to the tau protein itself, which physically interacted with glycogen and prevented its breakdown. The result was a toxic cycle: tau caused glycogen to build up, and the glycogen buildup made the tau accumulation worse.

When the researchers restored activity of an enzyme called glycogen phosphorylase (GlyP), which initiates glycogen breakdown, the effects were striking. In both flies and human neurons, breaking down glycogen reduced oxidative stress, lowered tau burden, and prevented cell death. It also extended the lifespan of tau-expressing flies by nearly 70 percent.

Rather than fueling energy production through glycolysis, the glycogen-derived glucose was diverted into the pentose phosphate pathway. This pathway produces antioxidant molecules like NADPH and glutathione, which protect cells from damage caused by reactive oxygen species. The researchers confirmed that oxidative stress levels dropped sharply in cells with active glycogen breakdown. Blocking this pathway erased the protective effects.

The team also found that dietary restriction increased glycogen phosphorylase activity through a well-known signaling mechanism involving cyclic AMP and protein kinase A. Treating flies with a drug that mimics this pathway had similar effects to calorie restriction, reducing cell death and extending lifespan. This may help explain why drugs used to treat diabetes and promote weight loss—such as GLP-1 agonists—show early signs of benefit in Alzheimer’s trials.

“Sugar metabolism in neurons is different from what was previously believed,” Kapahi told PsyPost. “We found that stored sugars in brain cells can help reduce reactive oxygen species—harmful byproducts of normal metabolism.

However, when these sugars accumulate too much, they can bind to toxic protein buildups and make the condition worse. We identified a pathway that breaks down this sugar buildup in neurons.”

Proteomic and metabolomic analyses supported these findings. The researchers identified dozens of metabolic and mitochondrial genes affected by diet, tau, and glycogen metabolism. Importantly, they found similar changes in brain tissue from Alzheimer’s patients, including upregulation of enzymes involved in glycogen metabolism.

“Using a fruit fly model, our team uncovered a powerful link between a rich diet and the progression of Alzheimer’s-like symptoms,” Kapahi explained. “Under the leadership of postdoctoral researcher Dr. Sudipta Bar, we made a fascinating discovery: neurons in Alzheimer’s patients accumulate an unusual amount of glycogen—a complex sugar molecule not typically found in large quantities in healthy brain cells. Because of its complex structure, glycogen can attach to toxic proteins and may accelerate their aggregation.”

“Even more intriguing, Dr. Bar found that neurons metabolize glycogen differently than other organs, hinting at a unique metabolic vulnerability in the brain. He also identified key upstream proteins and signaling pathways that may be harnessed to prevent or reverse this harmful process. This unexpected connection between diet, sugar metabolism, and protein aggregation opens exciting new avenues for Alzheimer’s research and potential therapies.”

Although the results are promising, the study has several limitations. Most of the experiments were conducted in fruit flies or lab-grown neurons, which do not fully replicate the complexity of the human brain. While human data were used for comparison, more work is needed to confirm whether glycogen metabolism plays the same role in living patients.

It is also unclear whether glycogen accumulation is a cause or a consequence of neurodegeneration, or whether it occurs early enough in the disease process to serve as a useful therapeutic target. Long-term studies in animal models and clinical trials will be needed to explore whether enhancing glycogen breakdown can slow cognitive decline or improve brain health.

The researchers plan to continue exploring how glycogen interacts with tau and other proteins, and whether certain diets or medications can modify this process. “Our long-term goal is to develop therapeutic strategies based on our findings,” Kapahi said.

“In addition, we aim to explore the many questions this study has raised, such as: How does glycogen breakdown help rescue disease pathology? Which metabolic pathways are altered by glycogen breakdown? And how does glycogen bind to toxic proteins?”

“We would like to acknowledge the valuable contributions of Prof. Lisa Ellerby, Prof. Birgit Schilling, and Prof. Tara Tracy from the Buck Institute, as well as Prof. Nicholas Seyfried from Emory University, along with their lab members, for their support and collaboration in this study.”

-Eric W. Dolan

The study, “Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction,” was authored by Sudipta Bar, Kenneth A. Wilson, Tyler A. U. Hilsabeck, Sydney Alderfer, Eric B. Dammer, Jordan B. Burton, Samah Shah, Anja Holtz, Enrique M. Carrera, Jennifer N. Beck, Jackson H. Chen, Grant Kauwe, Fatemeh Seifar, Ananth Shantaraman, Tara E. Tracy, Nicholas T. Seyfried, Birgit Schilling, Lisa M. Ellerby, and Pankaj Kapahi.

Read more at PsyPost

 

Scientists make key Alzheimer’s disease breakthrough

 

Scientists investigating Alzheimer's disease have made a key breakthrough. They have identified a vital cellular mechanism driving the most common cause of dementia. American researchers say the breakthrough marks a "promising" target for drug treatments that slow, or possibly even reverse, the disease’s development.

A team from the Advanced Science Research Center at The City University of New York (CUNY ASRC) discovered the critical mechanism that links cellular stress in the brain to the progression of Alzheimer’s. The study, published in the journal Neuron, highlights microglia - the brain's primary immune cells - as central players in both the protective and harmful responses associated with the disease.

Microglia - often dubbed the brain's "first responders" - are now recognized as a significant causal cell type in Alzheimer’s pathology. However, the cells play a double-edged role: some protect brain health, while others worsen neurodegeneration.

Understanding the functional differences between these microglial populations has been a research focus for Professor Pinar Ayata, the study’s principal investigator. Ayata said: “We set out to answer what are the harmful microglia in Alzheimer’s disease and how can we therapeutically target them. “We pinpointed a novel neurodegenerative microglia phenotype in Alzheimer’s disease characterized by a stress-related signaling pathway.”

The research team discovered that activation of this stress pathway, known as the integrated stress response (ISR), prompts microglia to produce and release toxic lipids. The lipids damage neurons and oligodendrocyte progenitor cells - two cell types essential for brain function and most impacted in Alzheimer’s disease. Blocking the stress response or the lipid synthesis pathway reversed symptoms of Alzheimer’s in preclinical models.

Using electron microscopy, the research team identified an accumulation of “dark microglia” - a subset of microglia associated with cellular stress and neurodegeneration, in postmortem brain tissues from Alzheimer’s patients. The cells were present at twice the levels seen in healthy-aged people.

Study co-lead author Anna Flury said: “These findings reveal a critical link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease."

Flury, a member of Ayata’s lab and a Ph.D. student, added: “Targeting this pathway may open up new avenues for treatment by either halting the toxic lipid production or preventing the activation of harmful microglial phenotypes.”

The research team says their study highlights the potential of developing drugs that target specific microglial populations or their stress-induced mechanisms. Co-lead author Leen Aljayousi, a member of Ayata’s lab, added: “Such treatments could significantly slow or even reverse the progression of Alzheimer’s disease, offering hope to millions of patients and their families,”

-Stephen Beech

The Daily Sun, NewsBreak

Dementia: Possible Risk Factors

 

Nearly half of all dementia cases could be delayed or prevented altogether by addressing 14 possible risk factors, including vision loss and high cholesterol.

That is the key finding of a new study that we and our colleagues published in the journal The Lancet.

Dementia, a rapidly increasing global challenge, affects an estimated 57 million worldwide, and this number is expected to increase to 153 million by 2050 worldwide. Although the prevalence of dementia is on the decline in high-income countries, it continues to increase in low- and middle-income countries.

This third updated report of the Lancet Commission on Dementia offers good news and a strong message: Policymakers, clinicians, individuals and families can be ambitious about prevention and reduce dementia risk; and for those living with dementia and their caregivers, support their quality of life using evidence-based approaches.

The new report confirms 12 previously identified potentially modifiable risk factors from two previous reports, published in 2017 and 2020. It also offers new evidence supporting two additional modifiable risk factors: vision loss and high levels of low-density lipoprotein (LDL) cholesterol, often called “bad” cholesterol.

Our study of published evidence found that collectively, addressing 14 modifiable risk factors could potentially reduce the prevalence of dementia by 45% worldwide. Even greater risk reductions could be possible in low- and middle-income countries and for people with low income in higher-income countries given the higher prevalence of dementia, health disparities and risk factors in these populations.

The report further indicates that reducing these 14 risks can increase the number of healthy years of life and reduce the length of time with poor health in people with dementia.

Additionally, the report cites clinical trials showing that nonpharmacological approaches, such as using activities tailored to interests and abilities, can reduce dementia-related symptoms and improve quality of life.

We are a general internist and an applied sociologist and intervention scientist, and our work focuses on memory and wellness in older adults. Together with 25 other internationally recognized dementia experts under the leadership of psychiatry professor Dr. Gill Livingston, we carefully reviewed the evidence to derive recommendations for prevention, intervention and care.

Why it matters

The rapid growth of aging populations worldwide is a triumph of better public and personal health throughout the entire life span. Yet, given the lack of a dementia cure, this report highlights the importance of prevention as well as supporting quality of life for those with a dementia diagnosis.

In the new report, our team proposed an ambitious program for preventing dementia that could be implemented at the individual, community and policy levels and across the life span from early life through mid and late life. 

The key points include:

• In early life, improving general education.
• In midlife, addressing hearing loss, high LDL cholesterol, depression, traumatic brain injury, physical inactivity, diabetes, smoking, hypertension, obesity and excessive alcohol.
• In later life, reducing social isolation, air pollution and vision loss.

     Together, these add up to the Lancet Commission on Dementia’s estimate that 45% of dementia risk can be reduced. And an abundance of new research shows that when risk factors are addressed, such as exposure to air pollution, they are linked with improved cognition and likely reduction of dementia risk.

     New evidence supports the notion that in high-income countries, reducing dementia risk can translate to more healthy years, years free of dementia and a shorter duration of ill health for people who develop dementia.

What still isn’t known

     The 45% reduction in dementia risk across the world’s population is based on a calculation that assumes that risk factors are causal and can be eliminated. It shows how dementia prevention is critical and the impact it would have on individuals and families.

     The commission emphasized the need for more research to identify additional risk factors, test risk factor changes in clinical trials, provide guidance for public health efforts, and identify and evaluate strategies for implementing and scaling evidence-based programs that support people with dementia and caregivers.

   The updated report has worldwide public health and research impact and is being widely disseminated. It serves as a guideline to clinicians and policymakers and outlines new research directions.

The Conversation: The Research Brief is a short take on interesting academic work.

 

FDA approves Eli Lilly Alzheimer’s drug after months of delay

 

The Food and Drug Administration granted approval Tuesday to a closely watched Alzheimer’s drug, concluding that the benefits of modestly slowing the progression of the devastating disease outweigh its risks, drugmaker Eli Lilly announced.

The agency, in a surprise move in March, had delayed approval of the drug to further scrutinize its safety and effectiveness. Last month, a panel of independent experts unanimously endorsed the drug, setting the stage for the FDA’s sign-off.

Eli Lilly’s drug — Kisunla, the brand name for donanemab — is one of the few treatments developed for Alzheimer’s that modifies the underlying disease and will join just one other drug, Leqembi, on the commercial market. Kisunla — which was approved for treatment of early symptomatic Alzheimer’s disease — doesn’t halt the disease, but it has been shown to slow cognitive and functional decline.

“I think it’s likely to be the highlight of the year for us,” said Daniel Skovronsky, Eli Lilly’s chief scientific officer, noting that there are “few diseases that are as feared with as few treatment options” as Alzheimer’s. He said Kisunla will be available to patients in the coming weeks. The debates over such drugs have been particularly fraught because there is no cure for the affliction affecting more than 6 million Americans. 

The total cost of Kisunla will vary by patient depending on when they complete the treatment. That’s because once a scan shows a patient has minimal levels of amyloid, they can discontinue the treatment.

The estimated cost for a six-month course of the therapy is $12,522. A full year of treatment is protected to cost $32,000, according to the drugmaker. However, many people probably will not pay the full list price in part since Medicare is expected to cover the treatment for certain patients.

For some, the price could be higher than Leqembi’s estimated cost of $26,500 per year, although that treatment does not stop after the amyloid clears. Kisunla is the third amyloid-targeting drug to win the FDA’s blessing since 2021, following two treatments — Aduhelm and Leqembi — jointly developed by drugmakers Eisai and Biogen.

The approval of Aduhelm deeply divided the medical community, as critics argued that there was not enough evidence to show that the drug worked. The drugmakers stopped marketing Aduhelm after it fizzled commercially. But Leqembi received a warmer reception because later-stage data showed the treatment slowed cognitive and functional decline by 27 percent over 18 months, while Aduhelm had conflicting data.

Still, like the anti-amyloid drugs that came before it, donanemab has not been free of controversy. Three patients who received the drug in a clinical trial died of a complication from the drug. The condition, called ARIA, can cause the brain to swell or bleed. No such deaths occurred in the placebo group.

Critics have also said that donanemab’s benefits, while statistically significant, are modest. Members of the advisory committee cautioned that the risks and benefits could vary depending on patients’ genetics and the stage of their disease.

In briefing documents last month, the FDA had signaled that it was not overly alarmed by the drug’s safety profile, writing that the findings “are generally consistent” with the class of drugs that aim to reduce or eliminate amyloid plaques.

Though far from a cure, the recent Alzheimer’s drugs have kindled excitement among some researchers and advocates because of the potential to modify the course of the disease — effectively buying more time for those who suffer from it.

“Having multiple treatment options is the kind of advancement we’ve all been waiting for — all of us who have been touched, even blindsided, by this difficult and devastating disease,” Joanne Pike, head of the Alzheimer’s Association, said in a statement.

The drug is administered by infusion once a month. A key feature of Eli Lilly’s approach is that treatment with the drug could be discontinued once a patient’s amyloid levels are reduced to a certain level. That could reduce the burden on patients, but it remains unclear how testing for amyloid should be conducted.

The approval isn’t likely to give a meaningful boost to Lilly’s profits in the near term.The Indianapolis-based firm has a stock-market value of nearly $820 billion — the eighth-highest among publicly traded U.S. companies, and the most of any pharmaceutical firm, according to S&P Global Market Intelligence. The company’s rising stock price has largely been driven by the runaway success of its diabetes and weight-loss drugs, Mounjaro and Zepbound, respectively.

Still, the approval marks a significant success for Lilly and could buoy the prospects of other amyloid-targeting drugs, according to Wall Street analysts.

-The Washington Post

by Rachel Roubein

Rachel Roubein is a national health-care reporter for The Washington Post and author of The Health 202 newsletter, a daily morning tipsheet focused on health policy and politics. Twitter

by Daniel Gilbert

Daniel Gilbert joined The Washington Post in 2022 and writes about the business of medicine. He previously spent seven years as an investigative reporter for the Seattle Times, and before that covered business and energy for the Wall Street Journal. Twitter

 

 

A Possible Alzheimer's Treatment

 

• Sildenafil, a compound in drugs that treat erectile dysfunction and one type of hypertension, could be used to prevent and treat Alzheimer’s disease, the results of a new study suggest.
• Among people who already take sildenafil, the main ingredient in Viagra, the incidence of Alzheimer’s disease was significantly less than in people who did not.
• At least one expert warned that an observational study such as this may not be telling the whole story, and should be approached with caution.

The compound sildenafil is a main ingredient in Viagra, and it forms the basis of Revatio, a medication for pulmonary arterial hypertension. Now, a new study suggests sildenafil may also help in treating Alzheimer’s disease.

Researchers, led by the Cleveland Clinic, observed a 30% to 54% reduction in the incidence of Alzheimer’s disease among people who were taking sildenafil for erectile dysfunction or pulmonary arterial hypertension, compared to those who did not.

The study is published in the Journal of Alzheimer’s Disease.

Sildenafil lowers tau levels in the brain

Alzheimer’s disease is the most common type of dementia. The Alzheimer’s Association estimatesTrusted Source that about 6.7 million Americans are living with Alzheimer’s. It is the fifth-leading cause of death in the U.S., and its prevalence is expected to rise as the population ages.

According to the Alzheimer’s Association between 2000 and 2019, deaths from stroke, heart disease, and HIV decreased, whereas reported deaths from Alzheimer’s increased more than 145%.

Alzheimer’s is a progressive disease, getting worse over time, typically beginning with memory loss and ultimately leading to difficulties communicating with others, or responding appropriately to the environment in which one finds themselves.

The authors of the new study utilized computational models to parse the data for millions of patients in two medical databases, MarketScan Medicare Supplemental and Clinformatics. In the MarketScan database, the reduction in Alzheimer’s was 54%. In the Clinformatics database, it was 30%.

After sildenafil was identified as a drug of interest from the analyzed data, further research occurred in the lab. Working with brain cells from Alzheimer’s patients, researchers found that sildenafil lowered levels of neurotoxic tau proteins. Such proteins build up in the brain as Alzheimer’s progresses.

For many years, these tau proteins were coupled with amyloid plaques as likely causes of Alzheimer’s. However, the foundational research on amyloid plaques has been discredited. Even so, neurotoxic tau proteins are still considered to be a crucial aspect of Alzheimer’s.

They also observed that neurons they had exposed to sildenafil promoted improved brain function, cell growth, and also reduced inflammation and metabolic processes associated with the cognitive degeneration that occurs with Alzheimer’s.

PDE 5 inhibitors to treat Alzheimer’s?

Sildenafil, as a treatment for erectile dysfunction, is a phosphodiesterase type 5 inhibitor, or PDE 5 inhibitor.

Dr. Ozama Ismail, Ph.D., Alzheimer’s Association director of scientific programs, who was not involved in the new study, noted that there was a recent and large UK study that suggested PDE 5 inhibitors may be able to reduce the likelihood of developing Alzheimer’s, but “there is no evidence that these drugs are able to treat Alzheimer’s disease.”

As far as the current study goes, said Dr. Ismail, “This observational study is based on electronic healthcare records and cannot determine if the connection is meaningful without further exploration.”

“Further research and specifically designed clinical trials are a necessary step before considering phosphodiesterase type 5 inhibitors for Alzheimer’s treatment. Such trials would need to include diverse participants — including women — to conclusively determine if this class of drug can meaningfully treat Alzheimer’s disease,” said Dr. Ismail.

He also cited as an “important limitation” of this study that Alzheimer’s was not diagnosed “using ‘gold standard’ testing that included imaging biomarkers and/or assessment at autopsy.”

If sildenafil is helpful for addressing Alzheimer’s, suggested Dr. Neil Paulvin, it may have to do with “activating [the] pathway and increasing blood flow.”

The phosphatidylinositol 3-kinase (PI3K)/Akt pathwayTrusted Source is key to various cellular processes, and has been implicated in cancer, so understanding its mechanisms better could theoretically provide clues as to what occurs in Alzheimer’s. Dr. Paulvin was likewise not involved in the study.

Safety concerns about repurposing drugs

The identification of sildenafil is an example of what may be possible with computer searches for valuable molecules. Dr. Paulvin noted such searches have turned up drugs such as “gemfibrozil [for cholesterol control], astaxanthin [an antioxidant], [and] minocycline [for treating bacterial infections].”

“This study highlights a potential new avenue for drug repurposing. Repurposing of existing, already-approved treatments can be a valuable part of drug development because, through already-completed testing, we know much about their safety and side effects. This can sometimes reduce the length and cost of studies needed for the new indication,” Dr. Ismail said.

He noted, however, that Alzheimer’s disease is especially “complex and multifaceted.” As a result,” he noted, “it is likely that combination therapies targeting different mechanisms are needed.”

“When considering repurposing an existing drug as an Alzheimer’s treatment, however, it is often important to conduct new studies over longer periods of time and in older people that reflect the diversity of individuals living with Alzheimer’s disease,” Dr. Ismail explained.

He cited the Alzheimer’s Association Part The Cloud initiative that has already invested more than $68 million supporting 65 clinical trials. These trials are aimed at “targeting various known and potential new aspects of the disease, including new and repurposed treatments for Alzheimer’s and other dementia.”

He noted that the endeavor is focusing on different pathways to treatment, such as how immune responses affect Alzheimer’s-related brain changes, the manner in which brain cells utilize energy and fuel, how they remove debris, and how the brain’s blood supply is maintained.

As regards to sildenafil, Dr. Ismail stressed that people should not use such prescription medications or over-the-counter [supplements and products similar to] phosphodiesterase type 5 inhibitors in hopes of preventing Alzheimer’s or other types of dementia based on these preliminary findings. “Always consult your physician before starting or changing your medications,” he added.

 https://content.iospress.com/articles/journal-of-alzheimers-disease/jad231391