Tag: Alzheimer's disease

Categories : Neurodegenerative DiseasesTags :

Study Links Deep-sleep Loss to Alzheimer’s-related Protein Buildup

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As tau builds up in the brain, non-REM brain waves necessary for memory formation become erratic.

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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. 

Three columns of three images each that are PET scans of brains. Each column contains
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.” 

Source: University of California Berkeley

Categories : Neurodegenerative DiseasesTags :

Human-safe Drug Repairs DNA in a Mouse Model of Alzheimer’s

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Source: Pixabay CC0

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.”

Source: King’s College London

Categories : Neurodegenerative DiseasesTags :

Before the Memory Fades: Scientists Discover a Potential Early Warning Sign of Alzheimer’s

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New research suggests Alzheimer’s disease may affect the brain’s ability to adapt before memory problems become obvious, offering clues for earlier interventions.

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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.”

Source: Texas A&M University

Categories : Diet and Nutrition Neurodegenerative DiseasesTags :

Fish Oil Supplements May Not Prevent Alzheimer’s-related Decline

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New clinical trial results show supplements with omega-3s have no effect on memory or cognitive function in older adults at risk for Alzheimer’s disease

Photo by Aleksander Saks on Unsplash

Fish oil supplements are purported to have cognitive benefits from the omega-3 fatty acids they contain, essential nutrients that help form neuron connections. But a new Keck Medicine of USC study published in eBioMedicine suggests that increasing omega-3 levels via supplements has little effect on brain health despite showing evidence that the nutrients directly reach the brain. 

The two-year, placebo-controlled, double-blinded study of older adults with an elevated risk of developing Alzheimer’s showed that high doses of omega-3s did not improve memory, cognitive function or brain cell loss in areas of the brain related to Alzheimer’s. 

“We all wish there was a silver bullet for preventing Alzheimer’s, but our findings showed that fish oil supplements do not appear to protect brain health,” said Hussein Naji Yassine, MD, director of the USC Center for Personalized Brain Health and lead investigator of the study. “While omega-3s play an important role in forming brain cell connections needed for cognition, our results do not support fish oil supplements as a preventive measure against Alzheimer’s.” 

How the study was conducted 

Researchers recruited 365 adults, ages 55 to 80 who rarely ate fish, which is rich in omega-3s, and who study authors considered at risk for Alzheimer’s. About half (47%) carried an APOE4 gene, the strongest genetic risk factor for late-onset Alzheimer’s. Participants were randomly chosen to receive either daily fish oil supplements or a placebo. The supplements contained 2000mg of docosahexaenoic acid (DHA), a key omega-3 involved in brain function. 

Researchers were first interested to learn whether the omega-3 in the supplement was able to reach the brain.  

They measured DHA levels in cerebrospinal fluid, which surrounds the brain, and found an average 17% increase of DHA levels in patients’ brains after six months, confirming the omega-3 reached its intended target. 

Next, researchers tested participants’ memory and cognitive abilities at the beginning of the study and again two years later. Study participants who took DHA supplements did no better on the tests than those who took a placebo. Brain scans also showed that supplements did not prevent shrinkage of the hippocampus, a brain region important for memory that is often used as a marker of brain aging and Alzheimer’s risk. 

Looking beyond supplements 

Now, Yassine and his team are focused on solving why omega-3 supplements can reach the brain but not affect brain health. Based on their previous research, they believe omega-3s may work better as a part of a Mediterranean-style diet, which is naturally rich in omega-3s and linked with lower Alzheimer’s risk, than in a standalone supplement. 

“We’re focused on better understanding how the brain processes omega-3s and whether factors, such as poor health, dietary pattern, genetic risk and age, may change the brain’s ability to effectively absorb and use omega-3s,” said Yassine. “We are working to develop medications that may help the brain better utilise these nutrients to preserve cognitive function.”  

Holistic lifestyle remains the best prevention  

While out of scope of the study, the researchers stress that overall healthy living – rather than relying on fish oil supplements alone – is the best way to protect brain health.

“Staying healthy throughout life remains the most powerful tool we have for reducing Alzheimer’s risk, including regular exercise, quality sleep and a balanced diet,” said Yassine. “Living a healthy lifestyle is the brain’s equivalent of getting regular car maintenance and high-quality oil changes. The brain is more likely to lose greater function if health issues in other parts of the body go unaddressed, in the same way that car engines stop working if regular maintenance is skipped.”

Source: Keck Medicine of USC

Categories : Neurodegenerative DiseasesTags :

Alzheimer’s Drug Analysis May Lead to Massive Overestimate of Effectiveness

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Brown University researchers say an analytic method can exaggerate the causal link between amyloid reduction and cognitive benefits of new Alzheimer’s drugs.

Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH

By Juan Siliezar

A statistical approach being used to support a new class of Alzheimer’s drugs may lead to overstated claims about how the drugs work, according to a new study led by researchers at the Brown University School of Public Health.

Published in JAMA Neurology, the research letter focused on quantile aggregation, a new statistical technique that divides people into groups, averages their results together and then looks for patterns across those groupings.

The letter examined how the approach works when applied to cognition and amyloid, a protein that builds up in the brains of people with Alzheimer’s disease. The approach was originally published in an analysis of Eli Lilly and Company’s Alzheimer’s drug donanemab.

“Many researchers believe reducing amyloid buildup could slow memory loss and cognitive decline associated with the disease, making it a major target for newer Alzheimer’s drugs,” said the study’s senior author Sarah Ackley, who is an assistant professor of epidemiology in the Brown University School of Public Health and runs the Computational Epidemiology Lab. “The problem is that using this method to assess the effect of amyloid removal on cognition can produce misleading results.”

The researcher’s concern is that the approach can make the link between amyloid reduction and cognitive improvement appear much stronger than it is, according to the analysis. The study the researchers looked at was a reanalysis of the original data from the randomised control trial on donanemab. It was  led by scientists affiliated with the drug maker.

“When we did simulations, we found that you could basically take a very weak relationship between amyloid and cognition and make it appear as something that looked really strong and important,” Ackley said.

The team expected there might be problems with the method but were struck by how large the effects were.

In simulations that were designed to reflect the conditions from recent trials, the team found the method showed the relationship between amyloid and cognition to be 29 times higher than its actual magnitude.

The researchers said this happens because by combining large groups of patients and averaging their results together, the process hides variability in cognitive change between patients. That can make it look like reducing amyloid is more predictive of cognitive benefit than it is.

The method also combines patients who received the drug with those who received a placebo. Without that randomization, the analysis cannot reliably determine whether amyloid reduction is actually causing cognitive benefit or whether other factors are at play, according to the study.

To illustrate this, the team also tested quantile aggregation using data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease Study that ran from 2014 to 2023.  That trial tested if the drug solanezumab could slow cognitive decline in older adults with elevated amyloid levels in their brains, an early sign associated with Alzheimer’s disease.

The trial showed solanezumab did not slow cognitive decline, yet when the team ran the data from that trial through the analysis of donanemab using the quantile aggregation method, it came back showing a strong link between lower amyloid and better cognitive outcomes.

“We basically built a case that this method is going to give you misleading results,” Ackley said. “It made a failed trial look like it had successfully removed amyloid and that the removal of amyloid had reduced cognitive decline. In reality, the drug did neither of these things.”

Ackley emphasized that the findings do not settle the broader question of how the new Alzheimer’s disease drugs work. Instead, she says, the work highlights a need for more rigorous statistical methods.   She also emphasized the need for more data sharing in Alzheimer’s research, especially as new  treatments become more widely used and covered by public programs like Medicare.

“Our study was simple, but a great demonstration of the value of academic research,” she said. “Working outside of industry incentives gave us the freedom to closely examine a methodological issue affecting how some of the most consequential new drugs are understood.” 

Source: Brown University

Categories : AgeingTags :

Alzheimer’s Risk Gene APOE4 Silently Undermines Bone Quality in Women

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Buck Institute researchers discover a surprising connection between a major risk factor for Alzheimer’s

Photo by Karolina Grabowska on Pexels

Scientists at the Buck Institute for Research on Aging, along with collaborators at UC San Francisco, have discovered that APOE4, the most common genetic risk factor for Alzheimer’s disease, causes bone quality deficits specifically in female mice, through a mechanism that is invisible to standard imaging and can emerge as early as midlife.

The findings, published in Advanced Science, reveal an unexpected biological link between Alzheimer’s risk and skeletal health, and identify a new molecular pathway that could one day inform earlier diagnosis of cognitive decline or guide treatment for bone quality loss in women who carry the APOE4 gene.

“What makes this finding so striking is that bone quality is being compromised at a molecular level that a standard bone scan simply will not catch,” says Buck professor Birgit Schilling, PhD, a senior author of the study. “APOE4 is quietly disrupting the very cells responsible for keeping bone strong, and it is doing this specifically in females, which mirrors what we see with Alzheimer’s disease risk.”

Physicians have long observed that people with Alzheimer’s disease suffer bone fractures at higher rates, and that a diagnosis of osteoporosis in women is actually the earliest known predictor for Alzheimer’s. But the underlying mechanism connecting brain and bone health has remained elusive.

To investigate this connection, researchers, led by research scientist and co-first author of the paper Charles Schurman, PhD, first performed a proteomic analysis of aged mouse bone, a comprehensive survey of all the proteins present in the tissue. “The team discovered that bone, and particularly osteocytes, the long-lived cells embedded within it, is unusually rich in proteins associated with neurological disease, including apolipoprotein E [APOE] and amyloid precursor protein,” says Schurman. “Notably, APOE expression in osteocytes was twice as high in aged female mice as in young or male mice.”

The team then turned to a humanised mouse model carrying either APOE2 (associated with reduced Alzheimer’s risk), APOE3 (considered neutral), or APOE4 (the risk variant), and analysed bone and hippocampal tissue from the same animals. APOE4 produced strong, sex-specific effects on both the bone transcriptome and proteome; researchers found the protein-level disruption in bone was actually more pronounced than the corresponding changes in the hippocampus.

Despite the protein level disruption, cortical bone structure appeared normal under imaging. Researchers found that bone quality deficits arose not from changes in bone shape or density, but from APOE4’s suppression of perilacunar/canalicular remodelling, the process by which osteocytes actively maintain the microscopic channels that keep bone mechanically resilient. When this maintenance breaks down, bone quality deteriorates even when it looks intact.

“These results suggest that osteocytes could serve as early biological sentinels for age-related cognitive decline in women carrying APOE4,” says professor Lisa Ellerby, PhD, also a senior author of the paper. The Ellerby lab studies genetic risk factors for Alzheimer’s.  “We think that targeting osteocyte function may open a new front in preserving bone quality in this population.”

Researchers say there is a larger takeaway from this research that links brain and bone science.  “While we think this work is relevant for human patients with Alzheimer’s disease or with osteoporosis, this study also highlights the need for researchers to consider the human body as an entire system without isolating organs and diseases from each other,” says Ellerby.

Source: Buck Institute for Research on Aging

Categories : Neurodegenerative DiseasesTags :

Anti-amyloid Alzheimer’s Drugs Show no Clinically Meaningful Effect

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Researchers have found that the absolute effects of anti-amyloid drugs on cognitive decline and dementia severity were absent or trivial

Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH

Drugs that target amyloid beta proteins in the brain likely have no clinically meaningful positive effects, while increasing the risk of bleeding and swelling in the brain, a new Cochrane review has found.

People with Alzheimer’s disease have high levels of a protein known as amyloid beta in their brains, detectable before symptoms begin, but its role in disease progression is uncertain. Drugs have been developed to remove these proteins from the brain, under the theory that this would prevent or slow disease progression.

The new review examined data from 17 clinical trials with a total of 20 342 participants, all looking at the impact of anti-amyloid drugs on people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Proponents of these drugs have theorised that they would be more effective at these earlier stages before the disease has progressed.

Absolute effects “well below clinical threshold”

The research found that the absolute effects of anti-amyloid drugs on cognitive decline and dementia severity were absent or trivial, falling well below established thresholds for the minimum clinically important difference.

“Unfortunately, the evidence suggests that these drugs make no meaningful difference to patients,” said lead author Francesco Nonino, neurologist and epidemiologist at the IRCCS Institute of Neurological Sciences of Bologna, Italy. “There is now a convincing body of evidence converging on the conclusion that there is no clinically meaningful effect. While early trials showed results that were statistically significant, it is important to distinguish between this and clinical relevance. It is common for trials to find statistically significant results that do not translate into a meaningful clinical difference for patients.”

In addition to the absence of clinically meaningful effects, the review found that anti-amyloid drugs likely increase the risk of swelling and bleeding in the brain. This was observed in brain scans without any apparent symptoms for most patients, although any long-term effects remain unclear since reporting of symptoms was inconsistent across trials. 

Future research should focus on other pathways

On the basis of the evidence, the authors conclude that future trials targeting amyloid beta removal are unlikely to provide clear benefit to patients. They found that these drugs do successfully remove amyloid proteins from the brain, but this does not translate into meaningful clinical benefit. They recommend that future research on Alzheimer’s treatment should focus on other mechanisms, with numerous studies ongoing in other directions.

“I see Alzheimer’s patients in my clinic every week and I wish I had an effective treatment to offer them,” said senior author Edo Richard, Professor of Neurology at Radboud University Medical Centre. “Existing approved drugs offer some benefit for some patients, but there remains a high unmet need for more effective treatments. Sadly, anti-amyloid drugs do not offer this and bring additional risks. Given the absence of correlation between amyloid removal and clinical benefit, we need to explore other pathways to help address this devastating disease.”

Read the full review

Categories : Diet and Nutrition Neurodegenerative DiseasesTags :

High Meat Intake Linked to Lower Dementia Risk in APOE4

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Photo by Jose Ignacio Pompe on Unsplash

Older people with a genetic risk of Alzheimer’s disease did not experience the expected increase in cognitive decline and dementia risk if they consumed relatively large amounts of meat. This is shown in a new study from Karolinska Institutet published in JAMA Network Open. The results may contribute to the development of more individually tailored dietary advice.

APOE is a gene that affects the risk of Alzheimer’s disease. In Sweden, approximately 30 per cent of the population are carriers of the gene combinations APOE 3/4 or APOE 4/4. Among people with Alzheimer’s disease, those with these genotypes account for nearly 70 per cent.

When the Swedish Food Agency presented an overview of research on the link between diet and dementia last year, more research was requested to assess a possible link between meat consumption and the development of dementia.

‘This study tested the hypothesis that people with APOE 3/4 and 4/4 would have a reduced risk of cognitive decline and dementia with higher meat intake, based on the fact that APOE4 is the evolutionarily oldest variant of the APOE gene and may have arisen during a period when our evolutionary ancestors ate a more animal-based diet,’ says first author Jakob Norgren, researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.

The study followed more than 2100 participants in the Swedish National Study on Aging and Care, Kungsholmen (SNAC-K) for up to 15 years. All were aged 60 or older and had no diagnosis of dementia at the start of the study. The association between self-reported diet and cognitive health measures was analysed, adjusting for age, sex, education and lifestyle factors.

Twice the risk of dementia

At lower meat intake, the group with APOE 3/4 and 4/4 had more than twice the risk of dementia than people without these gene variants. However, the increased risk of cognitive decline and dementia in the risk groups was not seen in the fifth of participants who consumed the most meat. Their median consumption is estimated at approximately 870 grams of meat per week, standardised to a daily energy intake of 2,000 calories.

‘Those who ate more meat overall had significantly slower cognitive decline and a lower risk of dementia, but only if they had the APOE 3/4 or 4/4 gene variants,’ says Jakob Norgren. He continues: 

‘There is a lack of dietary research into brain health, and our findings suggest that conventional dietary advice may be unfavourable to a genetically defined subgroup of the population. For those who are aware that they belong to this genetic risk group, the findings offer hope; the risk may be modifiable through lifestyle changes. ‘

The study also shows that the type of meat is important.

‘A lower proportion of processed meat in total meat consumption was associated with a lower risk of dementia regardless of APOE genotype,’ says Sara Garcia-Ptacek, assistant professor at the same department, who together with senior lecturer Erika J Laukka is the study’s last author.

The findings also extend beyond brain health. In a follow-up analysis, the researchers observed a significant reduction in all-cause-mortality in carriers of APOE 3/4 and 4/4 with higher consumption of unprocessed meat.

However, the study is observational and needs to be followed up with intervention studies that can better demonstrate causal relationships.

‘Clinical trials are now needed to develop dietary recommendations tailored to APOE genotype,’ says Jakob Norgren. He continues:

‘Since the prevalence of APOE4 is about twice as high in the Nordic countries as in the Mediterranean countries, we are particularly well suited to conduct research on tailored dietary recommendations for this risk group.’

The research was funded by, among others, the Swedish Alzheimer’s Foundation, the Swedish Dementia Foundation, the Emil and Wera Cornell Foundation, the Leif Lundblad family and other philanthropists, the Swedish Research Council and FORTE. The researchers state that they have no related conflicts of interest.

APOE Gene Facts:

Apolipoprotein E plays a central role in the transport of cholesterol and fats in the brain and blood. The protein is encoded by the APOE gene, which exists in three main variants: epsilon 2, 3 and 4. These variants affect the risk of developing Alzheimer’s disease and cardiovascular disease. Each person inherits two APOE genes, one from each parent, giving six possible combinations (genotypes): 2/2, 2/3, 2/4, 3/3, 3/4 and 4/4.

Compared to the most common genotype 3/3, one 4 variant increases the risk of Alzheimer’s disease by about three to four times and two 4 variants by about ten to fifteen times, while the 2 variant is associated with a lower risk. However, the increase in risk varies between different ethnic groups.

Source: Belloy et al., JAMA Neurology, 2023

Source: Karolinska Institutet

Categories : Neurodegenerative DiseasesTags :

How the Brain’s ‘Memory Replay’ Goes Wrong in Alzheimer’s Disease

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Mouse brain section highlights amyloid plaques, seen as bright green flecks (due to staining). Credit: Shipley et al.

Memory dysfunction in Alzheimer’s disease may be linked to impairment in how the brain replays our recent experiences while we are resting, according to a new study in mice by UCL scientists. The researchers say their findings, published in Current Biology, could help scientists develop drug treatments targeting this impaired brain function, or help design new tests for early diagnosis.

Co-lead author Dr Sarah Shipley (UCL Cell & Developmental Biology) said: “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.

“We wanted to understand how the function of brain cells changes as the disease develops, to identify what’s driving these symptoms.

“When we rest, our brains normally replay recent experiences – this is thought to be key to how memories are formed and maintained. We found this replay process is disrupted in mice engineered to develop the amyloid plaques characteristic of Alzheimer’s, and this disruption is associated with how badly animals perform on memory tasks.”

The replay process, which occurs in the brain’s hippocampus, involves place cells firing in rapid sequences during rest. Place cells – discovered by Nobel prize-winning UCL neuroscientist Professor John O’Keefe – are neurons (brain cells) that represent specific locations. When we visit somewhere, particular place cells fire, and as we move the cells fire in a sequence. Later, when we rest, these cells reactivate in the same sequence, helping memories become ingrained.

For the study, the researchers were testing how well mice performed in a simple maze task, while monitoring their brain activity with sets of electrodes that could simultaneously track roughly 100 individual place cells.

In mice with amyloid pathology, the replay process was fundamentally altered. Surprisingly, replay events occurred just as frequently as in healthy mice, but their structure was disorganised. The normal, coordinated patterns of place cell activity that should reinforce memories were scrambled. The researchers also found that place cells in affected mice became less stable over time, with individual neurons no longer reliably coding the same locations, particularly after rest periods – precisely when replay should be strengthening these representations.

This disruption had consequences on memory tasks: affected mice performed worse in the maze, appearing to forget where they had already been and revisiting corridors that led nowhere.

Co-lead author Professor Caswell Barry (UCL Cell & Developmental Biology) said: “We’ve uncovered a breakdown in how the brain consolidates memories, visible at the level of individual neurons. 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.

“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. We’re now investigating whether we can manipulate replay through the neurotransmitter acetylcholine, which is already targeted by drugs used to treat Alzheimer’s symptoms. By understanding the mechanism better, we hope to make such treatments more effective.”

Source: University College London

Categories : Neurodegenerative DiseasesTags :

Empagliflozin and Nasal Insulin Improve Brain Health in Early Alzheimer’s Disease

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A clinical trial from Wake Forest University School of Medicine shows that two widely available medications, the diabetes drug empagliflozin (Jardiance) and intranasal insulin, safely improve brain health in people with mild cognitive impairment and early Alzheimer’s disease. The study, published in Alzheimer’s & Dementia, marks the first time empagliflozin has been tested in non-diabetic patients with Alzheimer’s disease. The results show promising effects on memory, brain health and brain blood flow.

The research addresses a critical treatment gap for patients with Alzheimer’s disease. While recently approved anti-amyloid drugs represent progress, their benefits are modest, and they’re unavailable to many patients due to side effects and medical contraindications. They also don’t address the upstream metabolic and vascular problems that drive disease progression or help restore brain function after damage occurs.

“Our study suggests that targeting metabolism can change the course of Alzheimer’s disease,” said Suzanne Craft, PhD, lead investigator and professor of medicine and director of the Wake Forest Alzheimer’s Disease Research Center. “For the first time, we found that empagliflozin, an established diabetes and heart medication, reduced markers of brain injury while restoring blood flow in critical brain regions. We also confirmed that delivering insulin directly to the brain with a newly validated device enhances cognition, neurovascular health and immune function. Together, these findings highlight metabolism as a powerful new frontier in Alzheimer’s treatment.”

The four-week trial enrolled 47 older adults (average age 70) with mild cognitive impairment or early Alzheimer’s disease. Participants were randomly assigned to receive intranasal insulin alone, empagliflozin alone, both medications together or a placebo. 

Both medications were safe and well-tolerated. Treatment-related side effects were mild and similar across all groups. Participants found the nasal insulin device highly feasible to use (4.6 out of 5.0), and compliance rates exceeded 97% for both medications throughout the study.

The results revealed different benefits for each medication. Intranasal insulin improved performance on sensitive cognitive tests that detect early memory and thinking changes. Brain imaging showed insulin treatment increased the structural integrity of white matter connections and changed blood flow patterns in memory-critical regions. The treatment also reduced plasma GFAP, a marker of astrocyte (support cells that maintain healthy connections between blood vessels and brain cells) dysfunction that’s elevated in Alzheimer’s disease. 

Empagliflozin had different effects. The medication significantly lowered cerebrospinal fluid tau, a protein that forms toxic tangles in the brain in patients with Alzheimer’s disease. It also reduced neurogranin and vascular markers linked to disease progression and changed blood flow in key brain regions. Empagliflozin also increased HDL cholesterol, showing its beneficial metabolic effects work even in non-diabetic patients.

Both medications influenced multiple immune and inflammatory proteins in cerebrospinal fluid and blood. The changes suggest the drugs help activate protective immune responses while reducing harmful inflammation. Intranasal insulin particularly affected proteins involved in the nasal-olfactory plexus, a newly discovered pathway that connects the brain’s waste-clearance system to immune systems throughout the body.

The medications work differently but target overlapping problems. Empagliflozin, originally developed for diabetes, improves how the body processes glucose and sodium. That leads to better insulin sensitivity and vascular health throughout the body and brain. The drug also reduces oxidative stress and inflammation while improving how mitochondria produce energy in cells.

Intranasal insulin uses a precision delivery device to send insulin directly into the brain through the nose, bypassing the bloodstream. Once there, insulin activates receptors throughout the brain that keep synapses healthy, support blood vessel function, maintain white matter integrity, and regulate immune responses. Previous studies showed that lower doses of intranasal insulin preserved brain glucose metabolism and slowed white matter damage over 12 months.

The trial used higher insulin doses than previous studies (160 IU daily versus 40-80 IU) delivered through a cartridge pump system developed by Aptar Pharma and validated in earlier brain imaging studies. This device provides precise, reliable delivery to brain regions involved in memory and cognition. Empagliflozin was given at the standard 10 mg daily dose used for cardiovascular conditions in non-diabetic adults.

People with Alzheimer’s disease often have insulin resistance in the brain alongside vascular problems that reduce blood flow and nutrient delivery. These metabolic and vascular disruptions speed up the accumulation of amyloid plaques and tau tangles while preventing the brain from clearing these toxic proteins. Both medications tested in this trial target these upstream problems. 

“We plan to build on these promising results with larger, longer studies in people with early and preclinical Alzheimer’s disease,” Craft said. “Because empagliflozin or intranasal insulin improved tau tangles, cognition, neurovascular health and immune function, we believe these treatments could offer real therapeutic potential, either on their own or in combination with other Alzheimer’s therapies.”

The complementary effects of the two medications could make them valuable additions to combination therapy approaches. Since both drugs are already FDA-approved for other conditions with well-established safety profiles, they could reach patients faster than entirely new medications would.

Source: Wake Forest University School of Medicine