Low-dose aspirin was associated with a 70 per cent lower risk of dementia among older people with a particular genetic profile, a new Monash University analysis has found, raising the possibility of a more personalised approach to dementia prevention.
The research, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, analysed genetic data from the landmark ASPREE Trial (Aspirin in Reducing Events in the Elderly), screening genetic scores in more than 13 500 individuals to investigate whether a person’s genes influenced aspirin’s effect on reducing dementia risk.
The strongest finding was linked to genetics that influence platelet count.
Researchers ranked participants according to their platelet-related genetic score.
Among participants in the highest 20 per cent for a platelet count genetic score, only 1 per cent of those taking aspirin developed dementia, compared with 3.3 per cent of those receiving placebo.
This represents about a 70 per cent lower relative risk associated with aspirin use.
However, aspirin also increased the risk of serious bleeding in this group.
Major bleeding occurred in 4.4 per cent of those taking aspirin, compared with 2.1 per cent receiving placebo.
“Previous trials found aspirin didn’t prevent dementia when everyone was considered together,” Dr Fransquet said.
“Our findings suggest there may be more to the story.
“In people with this particular genetic profile, we saw substantially fewer cases of dementia among those taking aspirin.
“It raises the possibility that genetics could one day help us identify who may benefit from a preventive treatment, rather than taking a one-size-fits-all approach.”
Dementia Australia estimates 446 500 Australians are living with dementia in 2026.
It projects this will rise to more than one million by 2065.
While scientists have previously identified a link between platelet activation and aggregation and dementia, the role of a person’s overall platelet count has been less clear.
“What’s particularly interesting is that the signal wasn’t linked to the established genetic risk factors for Alzheimer’s disease and dementia,” Dr Fransquet said.
“Instead, it’s pointing us towards platelet biology and gives us a new avenue to investigate.
“We now need to confirm the finding in other studies and ultimately test it in a trial designed specifically for people with this genetic profile.
“People shouldn’t start taking aspirin to prevent dementia on the basis of this study without consulting with their doctor, particularly given the increased risk of serious bleeding.
“If it holds up, the fact that aspirin is already cheap and widely available could make personalised dementia prevention a real possibility.”
Study found distinct immune changes preceding multiple sclerosis relapse, providing new insight into how Epstein-Barr virus reactivation may trigger an MS attack in people with genetic risk factors
An electron micrograph showing three Epstein-Barr virus (EBV) particles colourised red-orange. Credit: NIAID
A new study illuminates the connection between the Epstein Barr virus (EBV) and multiple sclerosis (MS), pointing to a causal role for reactivation of the virus in triggering MS attacks in people with certain genetic risk factors. In a study of blood samples from more than 100 participants with MS, Mass General Brigham researchers detected increased EBV lytic activity in immune cells up to three months before MS relapse and discovered that these cells also showed elevated expression of genes linked to MS risk. The finding helps explain how a common virus and genetic risk may work together to trigger MS attacks. The work is published in Nature Medicine.
“These findings open a whole new avenue for targeted therapeutics,” said senior author Tanuja Chitnis, MD, director of the Translational Neuroimmunology Research Center and Chief of the Division of Neuroimmunology at Mass General Brigham. “Currently, most MS treatments work by broadly suppressing the immune system. Our results suggest there’s an opportunity to be more precise and develop approaches that target EBV or the immune cells involved in relapse.”
Researchers analysed blood samples from 114 patients with MS and 21 healthy participants in the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB) study, a decades-long MS cohort based at Brigham and Women’s Hospital, to track immune changes before relapse. The study included samples collected up to 90 days before participants experienced a relapse, allowing researchers to compare the pre-relapse immune state with periods of remission in the same patients.
To identify which immune cells changed the most before a relapse, researchers used single-cell RNA sequencing and other molecular techniques to analyse hundreds of thousands of immune cells. They found that B cells (immune cells that can house dormant EBV) showed some of the strongest changes, activating genes associated with antiviral responses, inflammation and EBV activity. The researchers also observed an increase of ABC-like B cells, a subset of cells linked to viral infections and autoimmune disease. They found that EBV proteins (derived from EBV genes) triggered MS risk genes to be expressed in immune cells prior to relapse, but not during remission or in healthy controls.
If these findings are validated in larger, prospective studies, blood biomarkers of EBV activity could help identify patients at increased risk of relapse, complementing MRI scans and existing blood biomarkers that typically detect disease activity only after inflammation is already underway. The authors note that future studies are needed to determine whether these findings extend to early-stage and progressive forms of MS.
“We believe this work provides foundational insights into the cause of multiple sclerosis,” said Chitnis. “This study puts all the pieces together, showing a timeline of how the reactivated virus interacts with risk genes to unleash inflammation before relapse
As we age, our episodic memory gets weaker. Sensory details of life’s moments – such as where we parked our car in a busy parking lot – become harder to recall, though scientists don’t yet know why. This is true for almost all of us, but for some people, including those who are developing Alzheimer’s disease, the scale of memory loss can be devastating.
New research by UC Berkeley neuroscientist Omer Sharon and colleagues, directed by former Berkeley sleep researcher Matthew Walker, may help explain why. The researchers identified a link between changes in brain wave patterns during non-REM sleep, poorer episodic memory formation and buildup of the protein tau, a known marker for development of Alzheimer’s disease, in the brain’s frontal cortex.
“This is the first time we’ve shown this relationship between tau and how it messes with memory consolidation by attenuating traveling slow waves that originate in the frontal cortex,” said Sharon, a postdoctoral researcher at UC Berkeley’s Center for Human Sleep Science. The findings were published in the journal Nature Neuroscience on Sept 11.
Many of us are familiar with the rapid eye movement phases of sleep, when slumbering people’s eyes flicker back and forth under their lids and most dreaming occurs. But non-REM sleep – a deeper form of sleep with little, if any, dreaming – is crucial for brain health.
During non-REM sleep, neurons shut down in slow, synchronised waves that move across the brain, beginning in the frontal cortex.
This coordinated shutdown has been observed only during deep sleep, and may be one reason why we sleep.
Omer Sharon, UC Berkeley Postdoctoral Researcher
“Each slow wave reflects an enormous population of neurons switching off and back on together,” Sharon said. “Our study shows that for memory, it’s critical that these events cascade in sequence across large parts of the brain. This coordinated shutdown has been observed only during deep sleep, and may be one reason why we sleep.”
As we age, tau proteins build up in many people’s brains. For them, these waves become irregular and less synchronised and travel shorter distances. This slow-wave breakdown is in turn linked to dwindling memory consolidation, cognitive decline and the development of Alzheimer’s disease.
To study this correlation, the researchers used electroencephalograms (EEGs) to measure brain waves during sleep. They compared results from cognitively healthy participants in their early 20s to those from their mid-60s to mid-70s. In the younger adults, clusters of slow brain waves traveled roughly the length of a handspan across the scalp during non-REM sleep. In the older adults, the waves traveled shorter distances and were more solitary.
Using positron emission tomography (PET) scans conducted with Dr. William Jagust, a professor emeritus in public health and neuroscience at Berkeley, the researchers traced radioactive markers injected into the bloodstream to measure brain function. The scans confirmed that the buildup of tau in the frontal cortex of older participants correlated with those long wave breakdowns.
In healthy older study participants, PET scans revealed the protein tau building up over time in their frontal cortices. This buildup correlates with shortened, isolated slow brain waves during sleep and with memory loss.Courtesy of Omer Sharon/UC Berkeley Department of Psychology
This interference with slow brain waves shows up even before patients develop Alzheimer’s disease. “These people did not have Alzheimer’s,” Sharon said. “They had tau in their brains, but with subclinical impacts. Their memory decline was within the normal range for their age.” Indeed, Alzheimer’s symptoms appear along a spectrum at first, Sharon said, with the amount of tau in a person’s brain correlating to cognitive performance.
The researchers also measured corresponding changes in memory consolidation by giving participants word associations at night, then testing how well they remembered them the next day. People with more solitary, shorter-reaching slow waves – what the researchers called “lonely waves” – remembered less material.
After several years, a subset of participants was retested. Those whose frontal tau had increased over the years had worsened slow-wave coordination and lessened overnight memory retention. While this does not prove that frontal cortex tau buildup causes memory loss, it indicates that there is a connection between the protein and episodic memory loss that is related in some way to brain wave changes.
PET scans are expensive and require specialised equipment, making them hard to arrange, so the researchers worked with neurologist Yo-El Ju at Washington University in St. Louis to measure tau levels in the spinal fluid of a different group of elderly people. Although this test didn’t reveal tau buildup specifically in the frontal cortex, a similar pattern emerged: The spinal fluid from participants whose brains had more solitary slow waves during sleep contained higher ratios of tau to another Alzheimer’s disease linked protein, amyloid.
Sharon found it convincing to see these different methods arrive at converging results. “It’s collected in a totally different place and in a different cohort, so I think that adds to the strength of the evidence,” he said.
Altogether, the multiple measures led the researchers to connect tau buildup, a known form of Alzheimer’s pathology, with a specific kind of brain function. “This longitudinal correlation suggests that Alzheimer’s disease pathology is associated with a disruption of this main sleep feature,” Sharon said.
And though it remains unclear to researchers why memory loss is correlated with aging, the findings suggest that the connection is more complex than previously thought. “It’s not just about age,” Sharon said. “It’s how much pathology you have in frontal areas where global waves originate.” It’s also about sleep quality – a hard-to-define concept for which slow waves seem to be proxies.
“We can see tau and lonely waves rising together over time,” Sharon said. “What we cannot yet say is which leads – and that question will shape how we design interventions.”
Use of hormone therapy later in life was associated with a lower risk of developing dementia, according to a study published August 12, 2026, in Neurology®, the medical journal of the American Academy of Neurology. The study does not prove that hormone therapy prevents dementia; it only shows an association.
“While these findings help us better understand the relationship between hormone therapy use and various markers of dementia, more research needs to be done before we can make recommendations to women about their use of these therapies in relation to their brain health,” said study author Jennifer Bruno, PhD, of Stanford Medicine in Stanford, California. “This study looked back at women who were using hormone therapy decades ago with the timing and type of use differing from what is current practice for most women today, so the results are informative, but they may not apply to today’s standards.”
For the study, researchers examined medical records from two large data sets. In total, the study reports data from 21 462 female participants from both groups who had clinical tests taken while they were living. A total of 728 participants from one data set completed brain scans or biomarker tests while they were living and 2959 participants from the other data set had autopsies after death, at an average age of 82, to look for signs of Alzheimer’s disease. Across both data sets, participants were followed for approximately three to five years, starting at an average age 71.
Of the total participants, 1953 participants took hormone therapy and 19 509 participants did not take hormone therapy. Those who used hormone therapy started using it when they were over age 70, on average. The researchers looked only at participants who took oestrogen-only therapy, since previous studies had indicated that oestrogen plus progestin combination therapy may increase the risk of dementia. In current standard practice, oestrogen-only therapy is prescribed only for those who have undergone a hysterectomy due to the risk of endometrial cancer.
Among the group with autopsy information available, participants who had taken hormone therapy were less likely to have signs of Alzheimer’s disease in their brains than those who had not taken hormone therapy. The autopsy assessment used a composite score that measures three hallmarks of Alzheimer’s disease: amyloid-beta plaques, tau tangles and neuritic plaques, which are amyloid plaques surrounded by damaged nerve cells.
Of those who had taken hormone therapy, 18% had no signs of Alzheimer’s disease in their brains at autopsy, compared to 10% of those who had not taken the therapy, and 40% of hormone therapy users had all three signs of Alzheimer’s disease, compared to 51% of those who had not taken the therapy. After adjusting for age, education, genetics, race and hypertension, researchers found that participants who took hormone therapy had 35% lower odds of signs of Alzheimer’s disease at autopsy when compared to those who did not take hormone therapy.
In a separate analysis using biomarker tests performed when women were living, those who used hormone therapy had levels of amyloid biomarkers in their blood and spinal fluid that indicated less amyloid buildup in the brain compared to women who did not take hormone therapy. Specifically, higher levels of amyloid-beta protein in blood and spinal fluid suggest that less of this protein was being deposited as plaques in the brain.
Finally, use of hormone therapy was also associated with 39% lower odds of receiving a clinical diagnosis of dementia and less risk of showing symptoms of memory problems or decline in functional abilities.
Bruno noted that the study participants who used hormone therapy had an average age of 70, which differs from current standard practice of starting hormone therapy usually in the late 40s to early 50s and stopping it before age 60.
“Despite these limitations, our findings provide evidence of an association between use of oestrogen-only hormone therapy during later life and better outcomes on dementia and brain health,” Bruno said.
Dementia is a condition caused by brain diseases and affects memory, thinking and the ability to function. More than 57 million people live with dementia worldwide and nearly 10 million people get newly diagnosed every year. Alzheimer disease is the most common form of dementia and is estimated to account for 60–70% of cases.
While there is no cure for dementia, up to 45% of the risks can be attributed to modifiable risk factors such as tobacco, alcohol use, social isolation, physical inactivity, air pollution and noncommunicable diseases (NCDs), including high blood pressure and diabetes. Beyond health, dementia affects a person’s independence, dignity and safety.
“We know more today than ever before about what drives dementia risk, and these guidelines translate that knowledge into action,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “Countries now have clear, evidence-based recommendations they can put into practice immediately to protect people’s cognitive health.”
WHO’s new guidelines reflect the latest evidence and innovations in dementia risk reduction providing proven interventions that can effectively lower dementia risk through early awareness and timely action. They represent an important opportunity to reduce the burden of dementia in the coming decades through stronger integration of services for noncommunicable diseases, mental health and brain health.
Reducing risk, preventing illness
The updated guidelines reflect significant growth in the evidence base since WHO first issued recommendations on dementia risk reduction in 2019. They provide consolidated recommendations on addressing unhealthy behaviours, managing medical conditions, and reducing exposure to environmental factors that may contribute to cognitive decline and dementia.
The guidelines recommend several healthy behaviours and lifestyle interventions to reduce dementia risk, including cognitive training and cognitive stimulation and engagement in social activities for adults who have normal cognition or are experiencing mild cognitive impairment.
The updated advice also includes interventions that reduce risk of NCDs, including increasing physical activity, stopping tobacco use, reducing alcohol consumption, adopting a healthy diet, and a new recommendation to reduce exposure to air pollution.
Management of cardiometabolic conditions such as hypertension, diabetes, and high cholesterol can also help reduce dementia risk. Further, hearing aids may be offered as part of risk-reduction strategies.
As an intervention to reduce the risk of cognitive decline and/or dementia, the guidelines do not recommend supplementation with vitamins B and E, omega-3 polyunsaturated fatty acids (PUFA) and multivitamins/minerals in the absence of a diagnosed deficiency, due to the lack of evidence of any potential benefits to outweigh unexpected harmful effects.
Human and economic cost
Dementia affects an individual’s ability to live independently, work and function, while placing substantial burdens on families and carers. It carries a major economic loss, costing the global economy an estimated US$ 1.3 trillion annually. About half of this cost is driven by unpaid care provided by families and friends. Understanding risk factors and taking action to prevent dementia can improve health and quality of life, helping people live longer, healthier and more independent lives.
A drug, that has previously been shown to be safe and tolerated by humans, reduces multiple disease-linked features of Alzheimer’s in a mouse model of the disease.
Neuroscientists from King’s College London have developed an approach that targets a key protein to tackle several features of Alzheimer’s disease in one go. They found that KCL-286, a drug that has previously passed Phase 1 safety trials originally developed for spinal cord injury, was able to lessen many disease-linked features of Alzheimer’s.
“KCL-286 is a first-in-class, orally bioavailable small molecule that has already successfully cleared Phase 1 human safety and tolerability trials. This will dramatically cut down the traditional multi-year timeline required for new drug development,” commented Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
The causes of Alzheimer’s disease are highly complex. It is classically characterised by toxic build-up of proteins called amyloid-beta and tau, ultimately resulting in neuron death. While amyloid-beta and tau have been the main targets for drug development, approved drugs targeting amyloid-beta alone have limited but measurable clinical success.
Other features of the disease, such as DNA strand breaks and inflammation, have only recently been investigated as potential disease-modifying targets. DNA damage and inflammation occur in the earliest stages of the disease, suggesting they may be important targets for treatment. The new drug was found to repair DNA breaks and reduce inflammation in a mouse model of Alzheimer’s disease, providing a broader therapeutic strategy than approaches focused on individual disease hallmarks such as amyloid and tau.
“Our findings demonstrate that KCL-286 not only targets DNA damage but also reduces inflammation, two processes that occur very early in Alzheimer’s disease progression. This highlights its potential as a disease-modifying therapy rather than simply addressing symptoms,” said Dr Maria Goncalves, who project managed the drug development.
The drug used in the new study, KCL-286, activates a specific protein in the retinoic acid pathway, a series of chemical reactions in the body used to process vitamin A. Previous studies have linked the deficits in this molecular pathway to amyloid-beta deposits forming in rat brains, similar to those seen in Alzheimer’s disease.
KCL-286 has previously been shown to help repair DNA double-strand breaks in neuropathic pain, leading researchers to hypothesise that it might be a suitable candidate for targeting the same type of DNA damage in Alzheimer’s disease.
DNA double-strand breaks are like a rope snapping completely in two, rather than just fraying at the edges. We found that KCL-286 promotes repair of these breaks, allowing us to target a key feature of Alzheimer’s disease.
Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
Shared molecular pathways between spinal acute spinal cord injury and Alzheimer’s disease, established by the same team at King’s, hinted that KCL-286, may lessen some markers of Alzheimer’s in neurons.
Natasha Hill, one of the first authors on the paper, said: “To develop an effective treatment for Alzheimer’s disease, we need to tackle multiple aspects of the disease. KCL-286 was able to target multiple disease-relevant cellular pathways, some of which are initiated very early in the disease course.”
A new study shows that a common virus can induce Parkinson’s-like brain damage and movement problems
Source: CC0
Scientists usually use animal models when studying Parkinson’s disease because these models mimic the disease well. They are limited, however, because they require either gene modifications or the injection of toxicants, which may not accurately represent how the disease occurs in humans.
But now, researchers at Texas A&M University have developed a model that uses a nontoxic way to generate the symptoms of Parkinson’s: infection with a virus called Theiler’s murine encephalomyelitis virus (TMEV), a natural pathogen in mice.
Their study is a game changer because it proves that a simple viral infection can trigger the exact brain damage and physical disabilities in animal models that are seen in people with Parkinson’s disease – and it sets the stage for additional studies.
“The toxic-exposure models are useful for studying Parkinson’s, but not all people who are exposed to chemicals go on to develop Parkinson’s, so these models cannot show all the ways a disease as complex as Parkinson’s actually begins or develops over time in people,” said Candice Brinkmeyer-Langford, a neurogenerative disease expert with the Texas A&M University School of Public Health at Texas A&M Health.
Parkinson’s affects more than 10 million people worldwide, making it second only to dementia among brain disorders. It destroys the cells that produce dopamine, a chemical essential for smooth body movement, leading to problems with balance and walking, tremors in the hands or fingers and overall stiffness, as well as mental or emotional distress.
Its origins are unknown, but for decades, experts have believed that the disease could be triggered by the brain inflammation caused by viruses – even those contracted decades earlier – as well as by a combination of a person’s genetics and environmental factors. This idea recently was affirmed by Brinkmeyer-Langford and others at Texas A&M in the case of another devastating motor neuron disease, amyotrophic lateral sclerosis (ALS).
“Viruses are known to cause entirely different diseases based on a person’s genetics,” she said. “For example, the Epstein-Barr virus causes mononucleosis, but may also contribute to cancer or multiple sclerosis, and SARS-CoV-2 can attack the heart and brain as well as the lungs.”
For this pilot study to test the validity of TMEV in studying Parkinson’s, the researchers conducted experiments to measure the following:
Brain cell infection and damage. One week after infection, the researchers confirmed that the virus had infected the dopamine-producing brain cells. At one month after infection, the dopamine-producing cells were destroyed in the site of viral infection. Dopamine-induced behaviours were compared between 13 infected animal models and 14 healthy control animal models after administering a dopamine-mimicking drug which produced a distinct movement pattern confirming dopamine neuron loss. This test confirmed that the virus caused a significant loss of these crucial dopamine brain cells over time.
Speed and coordination. They compared 13 infected animal models against 14 healthy control animal models to track and measure their motor skills with a standard assessment called the pole test to determine if losing dopamine-producing cells causes the physical movement problems typically seen in Parkinson’s patients. Animal models infected with TMEV had slower times to complete the test compared to the healthy control models, and this still was the case at week 20, when the study ended.
Gait abnormalities. They used a specialised treadmill, which evaluated over 100 factors involved in walking, motor function and balance, to analyse how quickly and efficiently the animal models walked. The test confirmed that the virus caused physical weakness following the loss of dopamine producing cells due to viral infection, proving that the virus damaged the brain in a similar way as seen in Parkinson’s patients.
Now that this innovative model has been proven, Brinkmeyer-Langford said future studies will include testing the TMEV model directly against standard, older animal models used in Parkinson’s research, looking for early warning signs and biological markers for Parkinson’s and analyzing how the body’s immune response to a virus changes the brain.
“The clock is ticking, since the rapidly aging global population means the number of people with Parkinson’s is expected to jump significantly,” she said.
New research suggests Alzheimer’s disease may affect the brain’s ability to adapt before memory problems become obvious, offering clues for earlier interventions.
When most people think about Alzheimer’s disease, memory loss is usually the first thing that comes to mind. Forgetting a loved one’s name, missing appointments or repeatedly misplacing everyday items are often considered early warning signs.
But what if the disease begins affecting the brain long before memory problems become noticeable? New research from scientists at Texas A&M Health suggests that another change in brain function may appear even earlier: difficulty adapting when circumstances change.
In a recent study, researchers found that animal models with Alzheimer’s-related brain changes developed problems with cognitive flexibility months before they showed signs of memory impairment. Cognitive flexibility refers to the brain’s ability to adjust behavior, learn new rules and adapt when situations change.
“We found that this function was impaired before we could detect deficits in spatial memory,” said neuroscientist Jun Wang, PhD, professor in the Texas A&M University Naresh K. Vashisht College of Medicine at Texas A&M Health.
The findings suggest memory loss is not always the earliest sign of Alzheimer’s disease. Instead, they suggest that by the time memory problems become noticeable, disease-related brain changes may already be underway. Paying attention to earlier changes in executive function may provide additional clues about the earliest stages of the disease.
Testing the brain’s ability to adapt
To investigate these early changes, researchers used a widely studied animal model of Alzheimer’s disease known as 5xFAD. These models develop amyloid-beta plaques, one of the key features found in the brain of humans with Alzheimer’s disease.
The research team focused on measuring cognitive flexibility through a method called reversal learning. In this type of test, animal models first learn that a particular action leads to a reward. Once that association is established, researchers change the rules and reward a different action instead.
Healthy animal models quickly adjusted and learned the new rule. 5xFAD models struggled to adapt, continuing to follow the original rule even after it no longer led to a reward. What made the finding particularly significant was that although they struggled to adapt to change, the animal models still performed normally on tests of spatial memory, which is the ability to remember where things are and helps us navigate our surroundings.
A hyperactive brain circuit
The researchers then discovered abnormally high activity in the medial prefrontal cortex, the region involved in decision-making, behavioral flexibility and goal-directed actions. This hyperactivity extended through a network connecting the prefrontal cortex and the striatum, two brain regions that work together to help people adjust their behaviour when circumstances change.
The team also found reduced activity in a specialised group of brain cells called cholinergic interneurons. These cells play an important role in learning and behavioral adaptation, and their decreased activity closely matched the cognitive flexibility deficits observed in the animal models.
Together, the findings suggest that Alzheimer’s disease may affect neural circuits involved in executive function and adaptability before causing noticeable memory problems.
Breaking a harmful cycle
Scientists have known that amyloid-beta production increases when neurons are highly active. At the same time, amyloid-beta can make neurons even more excitable. This creates a potentially harmful cycle in which increased brain activity promotes amyloid accumulation, which then drives even more activity.
Wang describes this cycle as a “chicken-and-egg” problem. To test whether breaking this cycle could help, the researchers used a targeted approach to quiet the overactive brain pathway. The method worked like a temporary “dimmer switch,” allowing the team to reduce the activity of selected brain cells in the front part of the brain that send signals to the striatum, a region involved in flexible behaviour.
The intervention improved cognitive flexibility, restored more normal patterns of brain activity and reduced amyloid-beta accumulation. The benefits persisted after treatment ended, suggesting lasting changes within the affected neural circuits.
Implications for Alzheimer’s research
Although the study was conducted in animal models and further research is needed to determine whether the same pattern occurs in humans, the findings point to a promising new direction for Alzheimer’s research and potential future treatments.
Rather than focusing exclusively on memory loss, scientists may need to pay closer attention to early changes in cognitive flexibility and executive function that may provide clues that Alzheimer’s-related changes are already underway. The findings also suggest that abnormal brain activity may be more than just a consequence of the disease. Reducing activity in the overactive brain circuit improved cognitive flexibility and reduced amyloid-beta accumulation, suggesting that targeting these neural networks could help slow disease progression.
Wang is hopeful that if future research confirms these findings, cognitive flexibility tests could potentially complement existing diagnostic evaluations. That may help identify people at earlier stages of the disease, perhaps years before more obvious memory symptoms appear.
“One thing that most people in the field agree on is that early diagnosis is extremely important,” Wang said. “Alzheimer’s disease is progressive. Neurons continue to degenerate over time. If we can identify the disease earlier, then treatment has a much better chance of helping.”
The image shows two halves of mouse brains: on the left, brain of an untreated mouse; on the right, brain of a mouse treated with the drug anle138b. It is clearly visible that the treated mouse has significantly fewer aggregates of mutant huntingtin. (Image: Miguel da Silva Padilha)
An experimental drug has been shown to alleviate symptoms of Huntington’s disease and extend lifespan in mouse models. Further studies are required to determine whether these results may also apply to humans.
The hereditary disorder Huntington’s disease has so far been considered incurable. Its clinical manifestations include impaired motor control and psychiatric symptoms. A new study offers promising insights. It shows that a specific drug candidate called anle138b can significantly reduce the toxic protein clumps in the brain that are characteristic of the disease.
Affected mice that were administered this compound retained their mobility for a longer time, their brains shrank less, and their lifespan was extended compared to untreated mice. Importantly, the compound not only alleviates symptoms but also addresses the underlying cause of the disease by preventing disease-specific harmful protein clumps from destroying nerve cells and their connections. These results were also confirmed in experiments with human stem cells from Huntington’s patients.
Promising Therapeutic Candidate
These are the key findings of a study that has now been published in the journal EMBO Molecular Medicine. The study was led by Professor Irina Dudanova, who holds the Chair of Anatomy and Cell Biology I at the University of Würzburg since April 2026, and her doctoral student Miguel da Silva Padilha. The substance was developed by the teams of Christian Griesinger, Director at the Max Planck Institute of Multidisciplinary Sciences in Göttingen, and Armin Giese from the Ludwig-Maximilians University in Munich, now at MODAG GmbH. Other participants of the study come from the Max Planck Institute of Biological Intelligence in Martinsried and the University of Cologne.
“Our data show that specifically targeting toxic protein aggregates with the compound anle138b is a promising approach for stabilizing neuronal health in the long term,” says Irina Dudanova, commenting on the study’s findings.
Cellular waste destroys nerve cells
Background: Huntington’s disease is an inherited movement disorder caused by a defect in a specific section of DNA, the gene that encodes the protein huntingtin. According to the health insurance organization AOK, approximately 10,000 people in Germany are affected by the disease. Several hundred new cases are diagnosed each year. A faulty repetition of the genetic code (known as CAG repeats) causes the huntingtin protein to take on an abnormal shape and form clumps.
The resulting protein aggregates can be thought of as a form of cellular waste that accumulates inside neurons. The protein aggregates disrupt vital cellular communication and lead to cell death, particularly in brain regions involved in for movement and cognition. An effective therapy that targets the underlying causes is not available. This is where the compound investigated anle138b comes into play, as it prevents the formation of the harmful structures.
The researchers investigated the efficacy of anle138b in two different mouse models: While one suffered from a severe, early-onset form of the disease, the other model mirrored the genetic situation in adult patients. The compound showed beneficial effects in both models.
A characteristic feature of Huntington’s disease is the loss of the protein PDE10A, which is found almost exclusively in the nerve cells that die in this disease. The amount of PDE10A decreases dramatically long before patients show the first severe symptoms. “If PDE10A levels drop, that is a clear signal that the disease is progressing. The protein is therefore well-suited as a biomarker for Huntington’s disease,” explains Miguel da Silva Padilha. If less nerve cells die, then the PDE10A levels stay high. This is exactly what the scientists observed: as a result of anle138b treatment, the concentration of PDE10A remained high in both mouse models.
Efficacy Demonstrated in Human Stem Cells
A key milestone of the study is the confirmation of these effects in human cells. “In our experiments with induced pluripotent stem cells – that is, precursor cells derived from Huntington patients’ cells – we also observed that the addition of anle138b reduced the amount of huntingtin aggregates,” says Irina Dudanova.
Since the compound targets a fundamental mechanism of protein aggregation, it is also of interest for research on other neurodegenerative diseases. Corresponding studies in mouse models have been so promising that two years ago a large clinical trial was started for the treatment of multiple system atrophy – a Parkinson’s-like disorder characterised by severe impairments of motor function, balance, and the autonomic nervous system.
Original publication
Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington’s disease. Miguel da Silva Padilha, Seda Koyuncu, Evangeline Chabanis, Sergey Ryazanov, Andrei Leonov, David Vilchez, Rüdiger Klein, Armin Giese, Christian Griesinger and Irina Dudanova. EMBO Molecular Medicine, DOI: 10.1038/s44321-026-00459-9
Salk Institute scientists discover chronoferroptosis, a chronic stress pathway in cells that causes neurons to become less resilient over time and more vulnerable to neurodegeneration
Representative neuronal cells are shown after acute iron exposure of six to eight hours (left) and after chronic iron exposure of nine days (right). The brain cell looks entirely different after chronic exposure, with dysregulated processes characteristic of the newly discovered cell stress pathway chronoferroptosis. Click here for a high-resolution image. Credit: Salk Institute
Neurodegenerative diseases affect tens of millions of people worldwide. Among these, Alzheimer’s and Parkinson’s diseases are the most common; in the United States alone, the Alzheimer’s Disease Association and Parkinson’s Foundation report roughly 7 million people with Alzheimer’s and another million with Parkinson’s. An intriguing clue lies in the tangled mystery of neurodegeneration that scientists are working to solve: iron accumulation.
Scientists have noticed that iron can slowly build up inside neurons. Early in life, this iron accumulation appears to have little effect on neuronal function. However, later in life, it can contribute to a slow neuronal demise. Salk Institute researchers studied nerve cells to figure out if and how this iron accumulation relates to neurodegenerative diseases. They found that the excess iron stuck in neurons lowers the cells’ defences, making them more vulnerable to stressors and other cellular insults through a process they named chronoferroptosis.
The study, published in Cell Death Discovery on June 18, 2026, points to iron accumulation as a key target in the effort to predict, prevent, and treat neurodegenerative diseases.
“Resilience has become a huge topic of discussion when it comes to Alzheimer’s disease and other neurodegenerative disorders, trying to make the brain more resilient in the face of stressors that contribute to neurodegeneration,” says senior and co-corresponding author Pam Maher, PhD, a research professor at Salk. “Our study reveals that cells lose resilience when iron hits a certain level, making neurons more susceptible to stressors that damage or even kill them.”
What do we already know about how the body uses iron, and is it linked to neurodegeneration?
Iron is an essential mineral for a healthy body. Found in dark leafy greens, starchy cereals, lean meats, seafood, and other common foods, iron helps red blood cells develop, carries oxygen around the body, makes hormones, and so much more, with a hand in everything from the immune system to energy production.
“It’s one of the most important minerals in the body,” says co-corresponding author Nawab John Dar, PhD, a postdoctoral researcher in Maher’s lab. “So, it isn’t the iron itself that is a problem with age. It is this accumulation of iron over time that is the problem.”
While the jury is still out on the exact mechanisms that initiate iron accumulation in neurons, the Salk team suspects the buildup is caused by a failure in the cells’ iron export machinery – iron enters neurons as usual but fails to get removed after use. But this failure doesn’t impact neurons for quite some time. The question is, why?
“People have been doing these experiments looking at iron exposure’s influence on cells over short 24- to 48-hour spans,” explains Dar. “But if neurodegenerative disorders are progressive, shouldn’t we have a cellular model that is progressive, too?”
Is iron accumulation making neurons less resilient?
Using a human-derived nerve cell line, the Salk team created the first progressive model of iron accumulation in neuronal cells. They compared the effects of both acute (between six and eight hours) and chronic (nine days) exposure to iron. What they discovered was an entirely new pathway, which they dubbed chronoferroptosis.
Maher has been studying ferroptosis for decades. Until now, ferroptosis was considered an iron-dependent cell death pathway, with cell death dependent on a process called lipid peroxidation. “It is like the cellular equivalent of when a cooking oil or nut goes bad. The fats in that oil or nut have undergone peroxidation,” explains Maher.
Chronoferroptosis adds the dimension of time to ferroptosis. To the researchers’ surprise, the pathway does not necessarily end in cell death. Instead, the findings reveal that ferroptosis can act as a cellular stress pathway.
In acutely exposed neurons, there was very little biochemical difference pre- and post-exposure to iron. However, in chronically exposed neurons, there were lots of changes: upregulation of some processes and downregulation of others; accumulation of harmful chemicals and depletion of helpful ones; and elevated lipid peroxidation. And when each exposure group was exposed to further stress, acutely exposed neurons could handle the stress, while chronically exposed neurons could not.
“We think these coordinated alterations in iron-handling and antioxidant defence proteins make chronically exposed neurons vulnerable to neurodegenerative pathology,” says Dar. “Entering this state of chronoferroptosis may set neurons up for age-related failure.”
How might chronoferroptosis inform neurodegeneration care?
By creating the first progressive model of iron accumulation in neuronal cells, the researchers were able to reveal surprising new clues in the case to crack neurodegeneration. “It’s not the amount of iron that seals the fate of these cells,” says Dar, “it’s the amount of time they spend under stress.”
Perhaps scientists will one day be able to detect when the brain begins entering this vulnerable state, when iron accumulation starts stressing neurons. They could then develop new interventions to address iron imbalances and keep neurons more resilient for longer.
“It’s not something we worked on in this paper, but our lab has developed several compounds to inhibit this pathway,” says Maher. “This could really be a promising therapeutic route for boosting neuron resilience and staving off neurodegeneration as we grow older.”
