When researchers examined physical activity levels, the pattern was striking. Those with the highest levels of activity in midlife and later life were 41–45% less likely to develop dementia than those who had the lowest levels of activity.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2841638
I’m always quite skeptical of animal models used in Alz. research because they’ve worked so poorly in the past.
In a new study, made available online on October 30, 2025, in Neurochemistry International, researchers from Kindai University and collaborating institutions discovered that oral administration of arginine, a naturally occurring amino acid and safe chemical chaperone, effectively suppresses Aβ aggregation and its toxic effects in animal models of AD. The researchers emphasized that although arginine is available as an over-the-counter dietary supplement, the dosage and administration protocol employed in this study was optimized for research purposes and does not correspond to commercially available formulations.
The research team included Graduate Student Kanako Fujii and Professor Yoshitaka Nagai from the Department of Neurology, Kindai University Faculty of Medicine, Osaka, and Associate Professor Toshihide Takeuchi from the Life Science Research Institute, Kindai University, Osaka.
In the mouse model, oral arginine significantly decreased amyloid plaque deposition and lowered insoluble Aβ42 levels in the brain. Moreover, arginine-treated mice showed improved behavioral performance and reduced expression of pro-inflammatory cytokine genes associated with neuroinflammation, one of the key pathological features of AD. These results suggest that arginine’s protective effects extend beyond aggregation inhibition to include broader neuroprotective and anti-inflammatory actions.
“Our findings open up new possibilities for developing arginine-based strategies for neurodegenerative diseases caused by protein misfolding and aggregation,” notes Prof. Nagai. “Given its excellent safety profile and low cost, arginine could be rapidly translated to clinical trials for Alzheimer’s and potentially other related disorders.”
Full story: https://www.eurekalert.org/news-releases/1106825
https://www.sciencedirect.com/science/article/pii/S019701862500155X
Chronic systemic inflammation is increasingly recognized as a contributing factor to various health issues, including neurodegenerative diseases. As people age, levels of inflammatory markers in the blood typically rise. Elevated levels of these markers often correlate with a higher risk of cognitive decline and conditions such as dementia. Scientists have established that diet is a primary way to regulate inflammation in the body.
Certain dietary patterns, such as the Western diet, are known to promote inflammation. These diets usually contain high amounts of red meat, processed foods, and high-fat dairy products. In contrast, diets rich in vegetables, fruits, and whole grains tend to lower inflammation. While previous studies have linked pro-inflammatory diets to memory problems and specific brain changes, the impact on overall brain aging remained less clear.
The researchers behind this new study aimed to fill this gap in knowledge. They sought to determine if a diet that promotes inflammation is linked to a comprehensive measure of brain health known as “brain age.” They also wanted to understand if this relationship varied based on a person’s chronological age or their genetic risk for dementia. Additionally, the team investigated whether systemic inflammation in the body acted as a bridge connecting diet to brain health.
A 20-year study published in the Journal of the American Medical Association found that adults who started using hearing aids before age 70 had a 61% lower risk of developing dementia. The study followed thousands of people and found the strongest benefits in those who treated their hearing loss early, before it became severe.
“Hearing loss can be gradual or it can be quickly overnight,” said Richard Phillips, a hearing instrument specialist with House of Hearing in Moab.
Researchers have found that a specific body profile—higher muscle mass combined with a lower visceral fat to muscle ratio—tracks with a younger brain age, according to a study being presented next week at the annual meeting of the Radiological Society of North America (RSNA). Visceral fat is hidden deep within the abdominal cavity, surrounding vital internal organs.
“Healthier bodies with more muscle mass and less hidden belly fat are more likely to have healthier, youthful brains,” said senior study author Cyrus Raji, M.D., Ph.D., associate professor of radiology and neurology in the Department of Radiology at Mallinckrodt Institute of Radiology at Washington University School of Medicine in St. Louis, Missouri. “Better brain health, in turn, lowers the risk for future brain diseases, such as Alzheimer’s.”
Brain age is the computational estimation of chronological age from a structural MRI scan of the brain. Muscle mass, as tracked by body MRI, can be a surrogate marker for various interventions to reduce frailty and improve brain health, and brain age predicted by structural brain images can lend insight to Alzheimer’s disease risk factors, such as muscle loss.
While it is commonly known that chronological aging translates to loss of muscle mass and increased hidden belly fat, this work shows that these health measures relate to brain aging itself,” Dr. Raji said. “It shows muscle and fat mass quantified in the body are key reflectors of brain health, as tracked with brain aging.”
For the ongoing study, 1,164 healthy individuals (52% women) from four sites were examined with whole-body MRI. The mean chronological age of the participants was 55.17 years. The researchers combined MRI imaging with T1-weighted sequences, a technique that produces images where fat appears bright and fluid appears dark. This allows for optimal imaging of muscle, fat and brain tissue. An artificial intelligence (AI) algorithm was used to quantify total normalized muscle volume, visceral fat (hidden belly fat), subcutaneous fat (fat under the skin) and brain age.
The researchers found that a higher visceral fat to muscle ratio was associated with higher brain age, while subcutaneous fat showed no significant association with brain age.
“Drains” in the brain, responsible for clearing toxic waste in the organ, tend to get clogged up in people who show signs of developing Alzheimer’s disease, a study by researchers from NTU Singapore has discovered. This suggests that such clogged drains, a condition known as “enlarged perivascular spaces”, are a likely early-warning sign for Alzheimer’s, a common form of dementia.
These brain anomalies can be visually identified on routine magnetic resonance imaging scans performed to evaluate cognitive decline. So, identifying them could complement existing methods to detect Alzheimer’s earlier, said Associate Professor Nagaendran Kandiah from NTU’s Lee Kong Chian School of Medicine who led the study.
The research, which studied nearly 1,000 people in Singapore, is also significant as it is one of the few globally to look at Asians, because most studies tend to focus on Caucasian participants. Asian studies are crucial as past research suggests that there are differences in dementia-related conditions between different ethnic groups.
Source: https://x.com/nick_krontiris/status/1993214047785734293?s=20
Open Source:
https://academic.oup.com/braincomms/article/7/6/fcaf389/8284626?login=false
EVOKE failed: Novo Nordisk shares plunge after Alzheimer’s drug trial fails to hit key target
The trial tested whether semaglutide — the active ingredient in Novo’s blockbuster diabetes and weight loss drugs Ozempic and Wegovy — helped slow progression for Alzheimer’s disease.
While treatment with semaglutide resulted in improvement of Alzheimer’s disease-related biomarkers in two separate trials, this did not translate into a delay of disease progression, Novo said in a statement Monday. The goal had been to slow patients’ cognitive decline by at least 20%.
Novo’s semaglutide gamble in Alzheimer’s draws a blank
The EVOKE and EVOKE+ studies enrolled 3808 participants suffering from mild cognitive impairment or mild dementia due to Alzheimer’s disease, who were randomised to receive oral semaglutide or placebo, both on top of standard of care.
Top-line results from the two-year primary analysis of the trials showed that semaglutide was not superior to placebo in reducing Alzheimer’s disease progression, as measured by the change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) score compared to baseline. The goal had been to slow patients’ cognitive decline by at least 20%.
Are all GLP-1RAs useless? Or does BBB penetrance matter? @DrFraser
My assessment is that once disease is significantly present, it is difficult to address. Furthermore, to date there is no Mendelian Randomization review of GLP-1 Agonists and AD or PD. The challenge there, would be that the gene would also be present in brain tissue and active life long.
I appreciate the limitations of the association type data analysis, but it is the best we have currently, and I don’t think 2 years of non-statistical benefits with a GLP-1 on a process that takes at least 20 years, maybe 30 years from onset to diagnosable AD (possibly shorter for PD) makes this the trial I’m interested in.
I’d be much more interested in individuals at risk of disease starting regular GLP-1’s 20 years or more before diagnosable AD or PD would be likely (tougher to predict with PD as most have no clear genetic cause), and see if incidence is decreased. The observational data would suggest a big rate reduction.
Much tougher doing a 20 or 30 year trial for obvious reasons.
If a Mendelian Randomization process is undertaken, that would leave us with the consideration, if a positive effect were found, that we’d only have certainty on GLP-1’s that cross the BBB.
I’m not discouraged by this trial, but think it reinforces the need to pursue multiple items that work on different pathways to risk reduce likelihood of disease. I’m doing at least 10 things, of which 5 I think have pretty good evidence. Some of these will fall off and be disproven, but if 3 of them end up panning out, I’ll be happy.
This is an interesting area:
Researchers have identified a new form of dementia that is often mistaken for Alzheimers but is less severe and doesn’t have the signature amyloid protein. Called LATE, for Limbic-predominant age-related encephalopathy, it affects about a third of people over 85. A mild condition on its own, when combined with Alzheimers it ravages the brain.
https://www.nytimes.com/2025/11/28/health/late-dementia-alzheimers.html
@adssx , you’ve probably already looked at this, but it seems like this might have potential in Parkinson’s also…
Open access Paper:
The owner of KetoneAid had me excited about this a couple of years ago. Their KE4 product is a great source of exogenous ketones. Their “Hard Ketones” can be a beer substitute (doesn’t taste that great though).
He has lots of reports of individuals with dementia symptoms who reportedly had marked improvement with this product.
As with many other things I’ve tried utilizing, my patient population didn’t seem to have any response to this treatment - however, I was utilizing it on individuals with a vague sense of mental sharpness decline, often in the setting of having an ApoE4 and being older.
Yes ketone drinks look interesting. There’s an ongoing trial in PD in the UK. I wonder if SGLT2i could achieve the same result as they shift the brain metabolism towards ketone use: Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics 2022
Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases
CAUTION: Chinese paper.
Pioglitazone reduces serum ketone bodies in sodium-glucose cotransporter-2 inhibitor-treated non-obese type 2 diabetes: A single-centre, randomized, crossover trial
From New Scientist:
Our brain wiring seems to undergo four major turning points at ages 9, 32, 66 and 83, which could influence our capacity to learn and our risk of certain
The brain has distinct regions that exchange information via white matter tracts – wiry structures made of spindly projections, called axons, that project from neurons, or brain cells. These connections influence our cognition, such as our memory. But it was unknown whether major shifts in this wiring occur throughout life. “No one has combined multiple metrics together to characterise phases of brain wiring,” says Alexa Mousley at the University of Cambridge.
To fill this knowledge gap, Mousley and her colleagues analysed MRI brain scans from around 3800 people in the UK and US, who were mostly white, and ranged in age from newborns to 90. These scans were previously taken as part of various brain imaging projects, most of which excluded people with neurodegenerative or mental health conditions.
The researchers found that among people who reach 90, the brain’s wiring has generally undergone five main phases, separated by four key turning points.
In the first phase, which occurs between birth and 9 years old, white matter tracts between brain regions seem to become longer, or more convoluted, making them less efficient. “It takes longer for information to pass between regions,” says Mousley.
This could be because our brain is packed with lots of connections as infants, but as we grow and experience things, the ones we don’t use are gradually pruned away. The brain seems to prioritise making a broad range of connections that are useful for things like learning to play the piano, at the cost of them being less efficient, says Mousley.
But during the second phase, between 9 and 32 years old, this pattern seems to flip, which is potentially driven by the onset of puberty and its hormonal changes influencing brain development, says Mousley. “Suddenly, the brain is increasing the efficiency of the connections – they become shorter, so information gets from one place to another more quickly.” This may support the development of skills like planning and decision-making, and improvements in cognitive performance, such as working memory, says Mousley.
Read full story: Your brain undergoes four dramatic periods of change from age 0 to 90
Open access paper:
