Unexpected benefit: SGLT2 inhibitors, used for diabetes, were linked to reduced dementia risk in psychiatric patients.
High-risk focus: Older adults with mood or psychotic disorders face higher dementia rates, but few prevention options.
Future implications: Researchers call for more trials to confirm benefits and explore metabolic-brain health connections.
Mr Stallard has been working for a decade to corroborate this revelation. His findings have, if anything, become even more striking. Last year he and some colleagues published research in the Journal of the American Medical Association showing that, whereas 40 years ago three in every ten Americans aged 85-89 had dementia, by 2024 just one in ten had it (see chart 1). What is more, America is not the only beneficiary of this trend. Between 1988 and 2015 the share of older people being diagnosed with dementia fell by 13% a decade across six countries in North America and Europe, according to a study of almost 50,000 people by Frank Wolters of the Erasmus Medical Centre in Rotterdam, and colleagues.
chart: the economist
Some smaller studies have also found big declines. Data from the Framingham Heart Study, which has tracked three generations in an American town, show an average drop in new dementia cases of 20% per decade over almost 40 years between the late 1970s and early 2010s. Those who were entering their dotage when Daft Punk’s “Get Lucky” was topping the charts (2013) were 44% less likely to have dementia than those who were doing so when Sting was urging Roxanne to switch off her red light (1978).
Whereas most earlier studies had simply pooled elderly people and then applied a statistical adjustment for age, Mr Stallard looked at narrow bands of ages to compare different cohorts of people over 50 years. By examining the changes between each successive cohort, he calculates that dementia rates have been declining by 2.5-3% for each calendar-year cohort. “In my view it was the Copernican revolution in the field,” he says, turning assumptions about dementia’s spread upside down. Similar cohort studies in various European countries and Japan have found comparable trends there, too.
Full story: How dementia is being defeated (The Economist)
The new study, published in June in JAMA Network Open, sought to determine whether healthy eating patterns could modify dementia risk in older adults with blood biomarkers indicating Alzheimer’s-related brain changes or other signs of brain cell damage.
To do so, the researchers analyzed data from adults without dementia, ages 60 and older, who took part in the Swedish National Study on Aging and Care. A total of 1,865 participants, with an average age of 70, were followed for up to 15 years.
At the start of the study, researchers measured three blood biomarkers linked to Alzheimer’s disease and other signs of damage or stress in the brain. They also assessed participants’ diets, lifestyle habits and health status, updating this information at follow-up visits three and six years later.
Participants’ diet information was used to assess adherence to three dietary patterns: a Mediterranean-style diet, the Alternative Healthy Eating Index and the Reverse Empirical Dietary Inflammatory Index, which measures the inflammatory potential of a person’s diet (a higher score denotes a more anti-inflammatory diet). Higher adherence scores for each dietary pattern indicate a higher quality diet.
Each diet pattern highlights different aspects of diet quality, and they all emphasize vegetables, fruits, nuts and whole grains while limiting more inflammatory foods such as red and processed meats and sugary drinks.
Better diets, especially less inflammatory ones, tied to lower dementia risk
Across all participants, healthier diet patterns were associated with a lower likelihood of developing dementia.
When the researchers analyzed participants according to their levels of blood biomarkers, however, they found striking results.
Greater adherence to all three diet patterns was generally associated with a lower risk of dementia among people with lower levels of blood biomarkers.
Full article: An anti-inflammatory diet may prevent dementia, even in people at higher risk, new study suggests
Apparently:
Intermittently inhaling a high dose of carbon dioxide seems to remove the proteins amyloid and tau, which are implicated in Alzheimer’s disease, from the brain by boosting its glymphatic system.
If it doesn’t kill you first.
For mind and body: Community gathering places may counteract cognitive disability
Effect Modification by Exercise Habit on the Association Between Participation in Community Gathering Places and Cognitive Disability
https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.70499
Guanfacine may aid in improving sleep caused by amyloid beta induced disruption of Alzheimer’s disease: “5xFAD mice displayed dark phase-specific hyperarousal and impaired brain state transitions by 2 months of age. LC neurons exhibited increased tonic firing due to impaired Kv4 and Kv7 potassium channel conductance, resulting from soluble amyloid beta (Aβ)-induced disruption of α2A adrenergic receptor regulation. Pharmacological activation of α2A adrenergic receptors restored Kv4/7 function and normalized LC excitability. Local administration of guanfacine (α2A agonist) or retigabine (Kv7 modulator) significantly rescued sleep-wake disturbances.” Impaired adrenergic regulation of Kv channels underlies LC hyperactivity and early-onset sleep disruption in AD-like amyloidogenic mice pubmed.ncbi.nlm.nih.gov
Crossposting:
The Alzheimer’s field is being turned on its head as mounting evidence points to the disease beginning outside the brain many years before symptoms start. This may mean we have to totally rethink how we approach preventing and treating the condition
Alzheimer’s disease has long been viewed as something that originates inside the brain, but an in-depth genomic analysis suggests it may initially be triggered by inflammation in distant organs like the skin, lungs or gut – perhaps decades before a person’s memory starts to decline. This radical reframing of the disease may explain why Alzheimer’s drugs have been disappointing to date, because they act too late in the disease process. Instead, we may need to redirect our efforts towards addressing inflammation in other parts of the body.
“As neuroscientists, we tend to be very brain-centric, but this study really shines a spotlight on the fact that the brain is not disconnected from the rest of the body, and when changes happen in the rest of the body, it affects how the brain functions,” says Donna Wilcock at Indiana University, who wasn’t involved in the research. “Even though Alzheimer’s is a brain disease, we need to think about the whole body when we think about how it begins.”
To explore the genetic underpinnings of Alzheimer’s disease, César Cunha at the Novo Nordisk Foundation Center for Basic Metabolic Research in Denmark and his colleagues studied genetic data from more than 85,000 people with the condition and 485,000 people without it from the European Alzheimer and Dementia Biobank. They also analysed gene activity in 5 million single cells from 40 areas of the body and 100 brain regions.
As part of this deep dive, the researchers examined 1000 genes with variants that increase the risk of Alzheimer’s disease. To their surprise, these seemed to show up far less in the brain than in other organs like the skin, lungs, digestive system and spleen, as well as in various types of immune cells circulating in the blood. “I kept looking at the graph and it seemed wrong because the expression of these genes in single cells in the brain was extremely low,” says Cunha. “But we ran more analyses and the more we looked at it, the more we realised they really weren’t in the brain, they were mostly in other parts of the body.”
Full article: Alzheimer’s may start with inflammation in the skin, lungs or gut (New Scientist)
If so, then this might explain, at least in part, the persistent findings that agents which do not cross the BBB or barely do, (like rapamycin), nonetheless often seem very impactful in various brain NDDs including dementias like Alzheimer’s. Those agents might act against inflammatory and other pathological processes in those tissues where AD might have etiological triggers. Food for thought - literally… if we posit that diet is associated with dementia, it need not affect the brain directly, just through a proxy like gut microbiome. It might all be connected, the body being an interconnected biological system.
This also keeps GLP1s very much in play, even with the disapointing results from the Novo trial that showed semaglutide did not slow down the disease once it set.
Alzheimer’s is a progressive brain disorder, and sleep disruption is a well-known feature of the condition. In a study of 60 people with the disease, higher levels of orexin in cerebrospinal fluid were associated with faster cognitive decline. Yet strong brain-wave activity during deep sleep appeared to weaken that connection. The authors stress that the findings are not proof of cause and effect and that larger studies are needed.
All participants were over age 60 and had mild or moderate Alzheimer’s. Each person spent one night in a sleep laboratory, and cerebrospinal fluid samples were collected the next morning. Over the following three years, those with higher orexin levels showed a quicker worsening of symptoms.
Brain Activity During NREM Sleep: A Closer Look
When researchers analyzed NREM sleep, they found that stronger sleep spindles and slow oscillations reduced the link between orexin and decline. Participants with more pronounced versions of these brain rhythms exhibited a much weaker association. Lower orexin levels also matched up with denser sleep spindles and longer slow oscillations.
Notably, orexin concentrations in cerebrospinal fluid were higher in women than in men. Still, the authors point out that the results cannot prove causality, and the lack of a healthy control group limits broader conclusions. The three-year pattern was inferred from just one night of sleep recording and a single cerebrospinal fluid sample.
Going forward, the team stresses the need for larger trials with more participants, more detailed sleep monitoring, and healthy controls to better understand how orexin, sleep, and Alzheimer’s disease interact.
Source Research Paper:
Hypercapnea (increased PaCO2) is a strong global vasodilator.
Done intermittently, it creates slow waves of vasodilation/vasoconstriction = vasomotion. This ends up being coupled to stimulating CSF movement = enhanced glymphatic/pervascular clearance → increase soluble beta amyloid from CSF to blood.
So yes, you’ll get higher blood levels after hypercapnea, especially with deep rhythmic breathing (to blow of the the CO2 in recovery) as that seems to further stimulated CSF flow.
The big question is whether clearing some of the soluble amyloid from your CSF makes any difference to the brain that is infiltrated with it?
The diseased brain remains, but yet you’ll move some of the soluble aspect of beta amyloid out into your blood stream.
Jon Brudvig PhD and I are doing a video on this exact topic, part 1 will publish in the next week. Part 2 will be me hooked up to an oximeter/capnography and testing some breathing techniques that would best generate cyclic hypercapnia and showing the data as we go.
The unknown is does this in anyway reduce brain amyloid burden?
I think the other fascinating discussion point on this, is whether this could be a mimetic of deep sleep. For example, if you were doing an international flight, couldn’t sleep, really wiped out after - could 30 minutes of cyclic hypercapnia get you restored as though you’d have deep sleep?
Initial symptoms of frontotemporal dementia (FTD) are easy to miss, since they can look more like a psychiatric condition than a neurodegenerative one.
September 4, 2026 at 6:00 a.m. EDT
If you’ve heard of frontotemporal dementia (FTD), it may be because of Bruce Willis or Wendy Williams — two celebrities whose diagnoses in recent years have shed light on this infrequently discussed neurodegenerative disease. Though FTD is relatively rare, accounting for about 5 percent to 10 percent of all dementia cases and affecting an estimated 50,000 to 60,000 people in the United States, it’s the most common form of early-onset dementia.
In fact, 60 percent of people who get diagnosed with it are ages 45 to 64, decades younger than the average person diagnosed with Alzheimer’s disease (which causes most cases of dementia). And yet, experts believe this is a significant undercount because it’s “rare enough that most medical providers, even specialists, don’t have experience with it, and so they don’t know what it looks like,” said Brad Dickerson, neurologist at the Mass General Brigham Neuroscience Institute and director of the Frontotemporal Disorders Unit at Massachusetts General Hospital.
The initial symptoms of FTD also diverge sharply from those of the more common Alzheimer’s disease because of the parts of the brain it attacks. FTD often starts “in the front of the brain, which is very important for behavior, regulation of social interactions, addiction, drive, organizing and planning,” said Bruce Miller, a professor of neurology and director of the Edward and Pearl Fein Memory and Aging Center at the University of California at San Francisco.
So, FTD generally manifests first with behavior or mood changes — rather than the memory loss and thinking problems of Alzheimer’s (which typically first affects the areas of the brain responsible for these tasks, including the hippocampus). It’s the reason FTD is often misread as a psychiatric issue, Miller said. On average, it takes about three to four years for people to get a diagnosis of FTD, according to the Association for Frontotemporal Degeneration.
Below, experts explain why FTD tends to hit earlier in life than other dementias, the often-overlooked signs to know and what care for people with the condition looks like.
FTD most often begins in the frontal lobe and its earliest symptoms typically include behavior or personality changes — called behavioral-variant FTD. The most common ones are easily mistaken as signs of psychiatric conditions such as depression or bipolar disorder, or dismissed as the effects of stress, burnout or even a midlife crisis. They include:
Read the full story: The dementia that often strikes in midlife — and the signs people miss
Conclusion from study:
“Despite the robust findings in this study, we note some limitations. To further enhance the applicability of these findings to human AD, validation can be conducted in additional human brains and in reductionist models of the human vascular niche. Furthermore, the known overlap of other comorbidities, such as diabetes and hypertension, could contribute to the observed relationships among fibronectin, VEGFA, HB-EGF, IGF-1 and AD pathology. Although we identified inflammation as one driver of fibronectin deposition, the specific inflammatory signals and their roles at different stages of the disease require further investigation. While this study establishes fibronectin as a mechanistic mediator of BBB dysfunction, the consequences of this pathway for cognition and higher-order brain function were not directly assessed and remain an important area for future investigation.”
GPT summary:
"The researchers identify an ECM component as a causal mediator of pathology and then partially reverse the pathology by manipulating it, which is much closer to the kind of ECM work we’ve been waiting for. Nature
The protein is fibronectin (FN1), an extracellular matrix glycoprotein. The researchers connect APOE4 to abnormal fibronectin accumulation around the brain vasculature:
APOE4 / amyloid / inflammation → astrocytes produce excess fibronectin → abnormal perivascular ECM deposition → disrupted integrin/FAK signalling → impaired VEGF, HB-EGF and IGF-1 signalling → blood-brain barrier dysfunction. Nature
That chain is supported unusually thoroughly. They combine human postmortem brain tissue, CSF and plasma data, single-cell transcriptomics, human iPSC-derived astrocytes, 3D human vascular models, zebrafish and aged mouse models. In 21 to 22-month-old APOE4 knock-in mice, brain fibronectin was almost double that of APOE3 animals. Nature
The intervention experiments are what push this over the line for me. Reducing fibronectin restored BBB integrity, and independently restoring the growth-factor signalling suppressed by excess fibronectin also rescued BBB function in experimental models. So the ECM alteration is not merely correlated with the disease state. Nature
There is also a fascinating human-genetics clue behind the whole project. Previous work identified a rare loss-of-function FN1 variant associated with a 71% reduction in Alzheimer’s risk among APOE4 carriers. The new study provides a plausible mechanistic explanation for why reducing fibronectin activity might be protective. Nature
Why I think it’s especially worth your time
This gets at something broader than Alzheimer’s.
Fibronectin is normally useful. It is an important part of wound healing and ECM remodeling. The problem appears to be excessive or misplaced deposition of an otherwise useful matrix protein, which then alters how neighboring cells behave.
That is exactly the sort of feedback relationship that makes ECM aging interesting. Aging cells remodel the matrix, but the remodeled matrix can subsequently alter signalling, vascular function, inflammation and cellular behavior. The ECM therefore stops looking like passive scaffolding and starts looking like another information-bearing component of the aged tissue environment.
The authors explicitly connect pathological fibronectin accumulation with broader vascular basement-membrane remodeling, impaired metabolic-waste clearance and neuroinflammation. They also note that the protective FN1 variant has been associated with reduced Lewy body disease risk, raising the possibility that this mechanism extends beyond Alzheimer’s. Nature
There are important limitations. They have not demonstrated that lowering fibronectin prevents dementia in humans, cognition was not directly tested in the experimental intervention, and several authors have patents related to FN1-targeted therapies and are founders/shareholders of KVM Therapeutics. Those conflicts are disclosed in the paper."
The preliminary analysis, published in Nature Metabolism, finds initial evidence that a popular supplement, taken by more than 40 million Americans, is associated with faster progression to dementia in people with early memory problems.
Glucosamine is a natural sugar-related molecule widely sold over the counter as a supplement in the US.
It is especially popular among older adults, who use it to support joint health and manage arthritis symptoms or joint discomfort.
But it may have an insidious downside for a certain subset of older adults.
Using electronic health record data, researchers at the University of Florida (UF) have now found that glucosamine use was associated with a 25 percent higher likelihood that mild cognitive impairment would progress to dementia.
“People take the supplement based on anecdotal reports that it improves joint health, especially in the knees,” writes biochemist Ramon Sun from UF for The Conversation.
Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy
Also, it’s almost worthless for its intended use. IMO benefits obtained are mostly placebo.
There’s already been a thread opened about this some time ago with a discussion. Maybe they can be merged.
