Predicting and Preventing Alzheimers & Dementia (and minimizing risk)

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#1073

Thx, will look into it more later I think.

The PI was the head of the Buck Institute I believe, a conservative and well regarded institution.

@A_User - thx

#1074

I downloaded my raw 23andMe data many years ago and found I was APOe 3/4. At the time, they measured it but they didn’t report it.

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#1075

Are you doing anything specific to mitigate this? The single biggest is reducing/eliminating alcohol

#1076

I don’t think you can say this - that alcohol is the single most important factor.

Yes, there is evidence that alcohol effects apoe4 carriers more than non carriers. Even this is somewhat mixed but most recent studies are consistent.

That doesn’t make alcohol the single most important thing.

The Lancet study for dementia risk factors had alcohol at 1% for excessive use. This is in contrast to 7% each for LDL and hearing loss. Sure - that wasn’t genotype specific but it is quite a leap to get from 1% to 7%. And excessive is not something people on a Rapamycin forum concerned about there apoe genotype are doing except perhaps one person.

My view of the data is still that LDL and hearing loss are most important even for carriers. Doesn’t mean alcohol is ignored for anyone let alone carriers.

Also, carriers represent about half of AD cases so the overall data that isn’t genotype specific is still 50% carriers. My point is that carriers are not that different from AD cases overall since they represent 1/2.

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#1077

You’re absolutely right - Gemini ranks alcohol cessation at number 8 along with smoking cessation.

Aerobic Exercise: 150+ minutes of weekly Zone 2 or high-intensity cardio.
Blood Glucose Control: Low-glycemic diet to maintain optimal insulin sensitivity.
Omega-3 Optimization: High DHA/EPA intake from fatty fish or supplements.Deep Sleep: 7–8 hours nightly to clear brain toxins via the glymphatic system.
Mediterranean/MIND Diet: Rich in leafy greens, olive oil, and antioxidants.
Cardiovascular Care: Maintain blood pressure at or below 120/80 mmHg.
Cognitive Stimulation: Continuous learning of new skills, languages, or instruments.
Substance Avoidance: Complete smoking cessation and minimal to zero alcohol intake.
Stress Reduction: Daily mindfulness, meditation, or cortisol-lowering practices.
Social Engagement: Regular active participation in community or group activities.

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#1078

On sildenafil to prevent Alzheimer’s: CrĂ©mieux: Viagra for Life Extension Does it work? I'm doubtful

Conclusion: probably useless per MR.

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#1079

Im quite hopeful the vit k has a role in prevention. And may also be able to reverse decline:

Scientists in Japan have created powerful new vitamin K-based compounds that may help the brain regenerate lost neurons

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#1080

On vitamin K and its analogs see also: Menaquinone-7 (MK-7): An interesting molecule to power up the mitochondria

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#1081

Flu drugs show promise against cognitive decline

Glycan Preservation Mitigates Viral Inflammaging and Neurocognitive Decline

Chronic viral infections like HIV accelerate biological aging and cause persistent neurocognitive deficits, even when antiretroviral therapy (ART) completely suppresses viral replication. A major piece of this pathogenic puzzle has been uncovered by identifying host glycomic degradation as a central driver of this decline. Cells are naturally coated in complex carbohydrate structures called glycans, with the sugars sialic acid and galactose acting as critical anti-inflammatory modulators. Sialic acid coats circulating glycoproteins and engages specific receptors on immune cells, triggering downstream transcriptional brakes that repress pro-inflammatory nuclear factor kappa B (NF-kB) signaling.

However, chronic viral status upregulates host glycan-degrading enzymes known as sialidases, which systematically strip these protective sugars away. This state of hypo-sialylation and agalactosylation removes the molecular brakes on the immune system, inducing persistent myeloid cell activation and chronic systemic inflammation, commonly referred to as “inflammaging”.

In clinical profiles of patients successfully managed on ART, this glycomic degradation directly corresponds with lower neurocognitive scores. Strikingly, this degradation signature is highly dimorphic, tracking far more aggressively in women than in men. This indicates that sex hormones or distinct immune architectures modulate how easily these protective sugars are stripped.

By deploying influenza neuraminidase inhibitors—which cross-react with mammalian sialidases—researchers successfully prevented the removal of sialic acid from cell surfaces. In complementary animal models, preserving the cell’s sugar coating effectively shielded the host environment. This intervention successfully blunted systemic and neuro-specific inflammatory cytokine cascades, normalized aberrant gene networks, halted advanced tissue-level epigenetic aging, and completely preserved spatial learning and working memory.

Actionable Insights

  • Repurposing Sialidase Inhibitors for Inflammaging: This study establishes a novel blueprint for utilizing established antiviral sialidase/neuraminidase inhibitors, such as oseltamivir (Tamiflu), as host-directed therapies to preserve the structural integrity of the glycome and quiet chronic sterile inflammation.

  • Quantifiable Epigenetic and Cognitive Benefits: * In vivo administration of sialidase inhibitors (oseltamivir combined with the experimental inhibitor DANA) significantly blunted virus-induced epigenetic age acceleration across multiple vital organs, showing a distinct drop in biological tissue age compared to untreated controls.

    • The treatment altered host microenvironments to reduce cell-associated viral DNA burden in the liver and lungs by roughly half (P = 0.0044 and P = 0.0178, respectively).

    • In spatial memory testing via the radial arm water maze, the therapy achieved near-total functional rescue, reducing working memory errors back to the performance baseline of uninfected controls (P < 0.0001 combined cohort).

    • Neuropathological markers exported via brain extracellular vesicles were radically suppressed, with significant parallel drops in Tau (P = 0.014) and Beta-amyloid (P = 0.0053) expression.

Source

  • paper: Inhibiting glycan degradation prevents HIV-induced inflammaging and cognitive impairment
  • Lead Institutions: Feinberg School of Medicine and the Potocsnak Longevity Institute at Northwestern University; Icahn School of Medicine at Mount Sinai.
  • Country: United States.
  • Journal Name: Med (Cell Press).
    Impact Evaluation: The impact score (CiteScore) of this journal is 13.0, evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a High impact journal.

Lifespan & Biomarker Data (Effect Size Calculation)

Because chronological lifespan was not tracked, the strength of the intervention must be assessed through its standardized effect on biological aging clocks and cognitive markers:

Primary Biomarker / Metric Control (Infected / Untreated) Status Treatment (Sialidase Inhibitor) Status Metric Strength & Statistical Verity
Epigenetic Age Acceleration Significant acceleration of biological age in lungs, liver, and spleen. Reversal of age acceleration across all analyzed tissues. Highly significant reduction in clock metrics (q = 0.0037 vs untreated infected group).
Spatial Working Memory Errors (RAWM) Severe cognitive deficit, averaging 4 to 5 errors per retention trial. Cognitive performance restored, averaging 1 to 2 errors. Near-complete behavioral rescue (Combined male cohorts: q < 0.0001; Cohen’s d estimated > 1.5).
Brain EV Tau Expression Elevated presence of neurodegenerative Tau protein in extracellular vesicles. Significant reduction back toward uninfected baseline parameters. Clear biomarker mitigation (P = 0.014 vs untreated infected cohort).
Brain EV Beta-Amyloid Expression High accumulation of Beta-amyloid in brain-derived vesicles. Expression heavily suppressed post-treatment. Pronounced therapeutic effect (P = 0.0053 vs untreated infected cohort).

The Practical Reality Check: Can You Use This Now?

No. While the concept of preserving the glycome to halt aging is highly promising, you cannot simply layer a protocol of current influenza drugs into a standard longevity regimen.

  • The Potency Problem: Commercially available sialidase inhibitors like oseltamivir (Tamiflu) and zanamivir were explicitly engineered to fit the molecular architecture of viral influenza neuraminidase. While they do cross-react with mammalian sialidases, they do so with significantly limited potency.

  • Toxicity and Dosing Risks: Because of this low binding affinity for human enzymes, a patient would require massive, sustained doses of oseltamivir to achieve meaningful glycan preservation in uninfected tissues. At those concentrations, the off-target effects and host toxicities would completely overshadow any theoretical longevity benefits.

  • Compounded Deficits: The paper notes that glycan loss is driven by a two-front war: increased degradation by sialidases and a decline in the expression of specific glycosyltransferases (the enzymes responsible for building the sugar chains). Inhibiting degradation only fixes half of the equation; it does nothing to restore a fading cellular capacity to synthesize these protective glycans in the first place.

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#1082

With all the (correct) cynicism about omega 3 supplements I was wondering whether weve lost sight of the clear signal on Omega 3 from fish as potentially the single biggest protection against dementia

The potential is astonishing - almost reducing your risk by nearly half. That’s enormous. And if you can do it with sardines or mackerel the risk is tiny.

I thought I’d get a Claude summary of the epidemiological evidence for us to discsuss

Omega-3 for brain longevity: what the evidence actually says (and why supplements miss the point)

I’ve been going down a rabbit hole on omega-3 and dementia prevention. Here’s what I found, with sources.

The headline numbers

The Framingham Offspring Cohort (1,490 participants, 7+ year follow-up) found that those in the highest quintile of red blood cell DHA (>6.1% of membrane fatty acids) had a 49% lower risk of Alzheimer’s disease compared to the lowest quintile — with an estimated 4.7 additional years of life free of AD. The original Framingham cohort showed an almost identical 47% reduction a generation earlier, in the same genetic pool. That’s a larger effect size than most pharmaceutical dementia prevention candidates.

A UK Biobank analysis of 217,000 adults confirmed a 35–40% lower risk of early-onset dementia in the highest omega-3 quintile, holding up after controlling for APOE genotype, exercise, BMI, education, and cardiometabolic factors.

The dose-response meta-analysis (48 longitudinal studies, 103,651 participants) found each additional 0.1g/day of DHA or EPA was independently associated with 8–10% lower cognitive decline risk — a continuous relationship with no obvious ceiling in the data.

Sources:

Why the RCT evidence looks weak but isn’t

The supplement RCTs have been largely neutral — but this is a methodological artefact, not a null result. The epidemiological cohorts showing 47–49% risk reduction were dietary studies, with participants eating oily fish 2–3x/week at intakes of 300–600mg EPA+DHA/day. The RCTs then gave supplements to mixed populations regardless of baseline omega-3 status — including many people already in the protective range — and unsurprisingly found no marginal benefit. When RCT results are stratified by baseline omega-3 index, effects reappear.

The target biomarker is the Omega-3 Index (EPA+DHA as % of RBC membranes): <4% is high risk, 4–8% intermediate, >8% optimal. Most Western populations sit at 4–5%. The protective Framingham quintile threshold was >6.1% RBC DHA alone.

Source: Importance of EPA and DHA Blood Levels in Brain Structure and Function - PMC

The whole food vs. supplement distinction matters biochemically

Fish delivers DHA primarily as lysophosphatidylcholine (LPC-DHA), which crosses the blood-brain barrier via a specific transporter (Mfsd2a). Fish oil supplements deliver triglyceride-bound DHA, which relies on a less efficient route. This may partly explain why dietary fish intake consistently outperforms supplements in observational data. A UC trial is currently running specifically to test this.

Source: UC trial compares omega-3 supplements for elderly adults at risk for dementia - University of Cincinnati: Founder of Co-op, Leader in Co-op | University of Cincinnati

Practical numbers for those who want them

For reference, approximate EPA+DHA per serving of common oily fish:

  • Tinned mackerel (M&S Danish/Collection, 110–125g): ~2,400–2,500mg
  • Tinned sardines (standard 100g tin): ~1,300mg
  • Hot smoked salmon (100g): ~800mg
  • Cold smoked salmon (100g): ~450mg

Two sardine tins + one mackerel tin per week = ~5,700mg/week (~814mg/day) — in the range of the protective dietary intakes in the cohort studies, and likely sufficient to achieve an omega-3 index >8% given the phospholipid bioavailability advantage of whole food.

The actionable test

Get your omega-3 index measured (OmegaQuant or equivalent). It’s the only way to know whether you’re actually in the protective zone — dietary estimates are notoriously unreliable, and individual absorption varies significantly. Given that this single biomarker is associated with nearly a 50% reduction in AD risk, it’s arguably one of the highest-value blood tests available for anyone serious about brain longevity.

Worth noting this all sits very comfortably alongside rapamycin’s mechanisms — mTOR inhibition, neuroinflammation reduction, and autophagy upregulation are complementary rather than overlapping pathways. DHA also has independent TFEB-activating properties in some models, though that literature is thin.

Happy to discuss sources or methodology — I went through the primary papers rather than review articles where possible.

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#1083

Brain lipidology: understanding APOE, cholesterol homeostasis, Alzheimer’s disease risk, and the effects of lipid-lowering therapies on brain health

Tom Dayspring is a world-renowned lipidologist and one of the most thoughtful teachers in the field of lipid metabolism. In this episode, Tom returns to The Drive for a deep dive into the relationship between lipids and brain health, beginning with the fundamentals of cholesterol transport before exploring why the brain’s cholesterol system operates almost entirely independently from the rest of the body. Tom examines the roles of apoB, apoA-I, and especially apoE in cholesterol homeostasis, discusses how APOE genotype influences Alzheimer’s disease risk, and unpacks the complex links between cholesterol metabolism, amyloid, and tau pathology. He also reviews what is currently known—and still uncertain—about the effects of statins, ezetimibe, omega-3 fatty acids, and emerging CETP inhibitors on brain health and neurodegenerative disease risk. Although highly technical, this conversation provides an essential framework for understanding the nuanced relationship between lipid-lowering therapies, cardiovascular disease prevention, and neurodegenerative diseases in an area often clouded by misinformation.

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#1084

Dementia risk linked to nitrate in drinking water, study finds

Date:
June 8, 2026

A major long-term study of more than 54,000 adults found that where nitrate comes from may matter far more than how much you consume. People who got more nitrate from vegetables—roughly the amount in a cup of baby spinach a day—had a lower risk of developing dementia, while higher nitrate and nitrite intake from red meat, processed meat, and even drinking water was linked to a greater risk.

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#1085
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#1086

I had just cancelled my subscription to Peter Attia’s podcast and two days later he posted this fantastic episode with Tom. Perhaps I’ll reconsider

#1087

So we’re basically better off drinking purified water, or at least taking some antioxidants when we do.

#1088

Remember that most of your magnesium comes from the water. If you start using a purifier you need to add it back:

Association between exposure to desalinated sea water and ischemic heart disease, diabetes mellitus and colorectal cancer; A population-based study in Israel

https://www.sciencedirect.com/science/article/abs/pii/S001393511830358X

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#1089

Low Plasma Vitamin C Linked to Lower Gray Matter and Neural Network Gaps

The team discovered that individuals over the age of 64 with depleted plasma vitamin C levels exhibit a lower overall volume of cerebral gray matter and severely decreased functional connectivity inside the Default Mode Network (DMN), the brain network that governs autobiographical memory, self-reflection, and continuous attention.

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#1090

Just reminders, all covered before in this thread and elsewhere


The midlife habits that could make or break your brain health long-term

Researchers increasingly believe the 40s, 50s and 60s represent a critical window for protecting cognitive health later in life.

Neuroscientist Miia Kivipelto’s life’s work has been about preventing dementia. Now, at 52, she has begun thinking more about her own vulnerability.

“Midlife is the time,” said Kivipelto, a neuroscientist who recently joined the Yale School of Nursing as the inaugural director of its Center for Aging Well in New Haven, Connecticut. “It’s the last best chance to lower risk.”

The idea that dementia prevention may hinge on what people do in their mid-30s to their 60s is rapidly reshaping the field. Scientists increasingly believe the disease is driven not only by changes in the aging brain, but also by years of metabolic stress, inflammation and vascular damage accumulating across the body. Many researchers now think the biological process that leads to dementia begins 15 to 20 years before the first memory problems emerge. By the time symptoms become noticeable, the disease likely will already be well established.

Neuroscientists now see midlife as a critical window when the brain becomes especially vulnerable to aging — but also more responsive to intervention.

The implications are profound: The ordinary habits of middle age may matter far more than scientists once realized, and cognitive decline may not be inevitable.

Last year, a large study in JAMA Network Open found that people who remained physically active during midlife had a 40 to 45 percent lower risk of dementia later in life. A meta-analysis of more than 3 million people published in April in PLOS One found that the greatest reductions in dementia risk came from how people behaved in midlife and were associated with seven to eight hours of sleep, at least 150 minutes of aerobic activity a week, and fewer than eight sedentary hours a day.

Taken together, the findings suggest a new pathway for addressing a growing societal problem. More than 57 million people worldwide are living with dementia, and researchers predict that number will nearly triple to more than 150 million by 2050, according to estimates published in the Lancet. Scientists now estimate that roughly 45 percent of cases could potentially be delayed or prevented through changes to modifiable risk factors.

“The younger you are, the greater the bang for the buck in terms of these behaviors and lowering your risk,” said Akinkunle Oye-Somefun, a research associate at York University in Toronto and a co-author of the PLOS One study.

Read the full story: The midlife habits that could make or break your brain health long-term (Washington Post)