Yes, i asked Claude to read the report but specifically NOT limit itself to the factors included in the Lancet report.
I’m not sure why we would limit this question to the Lancet report. The pharmaceutical sector is certainly not, Billions of dollars are being invested in areas factors not included in the Lancet report. So it would seem logical/obvious that there are many factors outside the limited remit of the Lancet report.
Essentially the Lancet Commission’s approach is conservative because the report is explicitly designed to inform policy and public health action at scale.
It’s not designed to identify the true modifiable vs non-modifiable risk factors of dementia. It wants to identify the low hanging fruit for policy makers.
Your Claude answer seems to be answering the wrong question if you’re trying to understand what the modifiable percentage of dementia will be in the future.
This is the part I most strongly disagree with. We have so many avenues of attack for solving this problem - and with AI assistance i expect huge progress.
Noting the recent report of an association between lower 25OHD levels and higher dementia (ie vitamin D earlier in life prevents dementia) I thought I would ask a question of chatGPT:
So the best summary is:
Sunnier / higher-UV countries tend to have lower age-adjusted dementia incidence in ecological analyses, but the association is vulnerable to confounding and diagnostic bias. The most plausible biological link is vitamin D plus circadian, sleep, inflammatory and vascular pathways, but causality is not established.
The safest interpretation is: low sunlight exposure is a plausible dementia-risk marker, not yet a proven country-level causal factor.
I think you may have misunderstood what the Lancet Paper is trying to do.
Dismissing the broader avenues (“clues”)(neuroinflammation, microbiome, protein clearance pathways, mitophagy, autophagy, immune modulation etc.) as BS just because the Lancet Report (a deliberately conservative policy document) didn’t include them yet is exactly the naive take I’m pushing back on.
Those broader areas have real mechanistic depth and serious money behind them for a reason. The Lancet identifies today’s public policy low-hanging fruit. It doesn’t try to define the true ceiling of what’s modifiable. It tries to definethe conservative, policy-gradelower bound.
So if the question is, what will the next Lacet Commission say meets this criteria for public policy, sure we should he pessimistic. But as to what is and will be truly modifiable that’s a whole different question.
And I’d bet a lot higher. The remaining 55% isn’t a brick wall, its not “non-modifiable”, it’s a research agenda. Is Urolithin A BS? or does it modify risk of dementia? We dont have hard RCT evidence yet, but I’d guess that its mitophagy affect does modify risk to some degree. But that’s not the point, the point is that mitophagy and brain mitochindrial health is one of many,many avenues/“clues” we have for improving ageing brain function and reducing risk of dementia. So the idea that we have “no clues” and will reach a low ceiling on what’s modifiable seems obviously wrong. Especially in an age of Alphafold and AI driven biology.
I said BS because most of those listed in your post were BS or promising but unproven. Others are promising and are included in the Lancet report (e.g. vaccines).
In any case the discussion was about “modifiable risk factors” and this is what the Lancet paper is about. They’re not conservative, they’re just looking at the real evidence beyond some hypotheses.
So my point is that in 2035 I don’t expect the scientific consensus (that the Lancet represents) to be that modifiable risk factors for dementia are more than 60%. I wish it could be the case but it’s unlikely. I would be willing to bet on that (it’s a safe bet for me because it’s like an insurance against science being slow ). Of course I would prefer to be wrong that we have to be realistic.
By the way, this article is about Alzheimer’s and dementia: for other forms of dementia such as Parkinson’s disease dementia, the modifiable risk factors are closer to 0%.
I was just making the point that the 14 modifiable risk factors listed in the Lancet paper are those with robust enough evidence to drive policy recommendations. That’s what the Lancet paper “is about” it restricts itself to where there is "Population Attributable Fraction ", trying to represent a scientific consensus of where there’s robust enough evidence to act at a population/policy level. That’s very different from trying to reach a scientific consensus as to biologically modifiable vs mon-modifiable risk factors.
The part we really disagree on though is whether we have “no clue” as to the other modifiable risk factors and therefore whether the modifiable risk factors % will reach a ceiling:
When it seems to me we have a huge number of clues and other factors to explore. A good example is nutrigenomics. I have PEMT TT so my liver doesnt synthesise phosphatidylcholine well and so i rely more on dietary choline (and supplements) than typical. Is that a modifiable risk factor for dementia? phophatidylcholine deficiency is very likely to be a big risk factor for dementia. And its easily modified for me - I eat eggs and take choline tablets. By 2035 I would certainly assume we’ll have much greater understanding around this specific area. But will it ever feature in the Lancet report? I doubt it - because it wont make sense at a population level. “Lack of Nutrigenomics” might feature, but i doubt even that.
I like your bet - its safe for me too because if you’re right probably neither of us will remember the bet!
If your example was correct then for sure it would appear in the Lancet report because it would be some kind of deficiency. But it’s also possible that in 2035 we’ll learn that choline supplementation or whatever other intervention increases the risk of dementia.
I asked GPT-5.5-thinking about epidemiological evidence for the effect of sustained ibuprofen use on Alzheimer’s risk reduction:
Its conclusion:
The epidemiologic case for sustained ibuprofen is moderate as an association and weak as causal evidence. The strongest ibuprofen-specific evidence is the large VA observational study showing a >40% lower Alzheimer’s risk after >5 years of ibuprofen use, but that result could be biased. Broader cohort/meta-analytic evidence supports a possible long-duration NSAID association, but not cleanly for ibuprofen alone.
Given the known harms of chronic ibuprofen—higher risks of heart attack, stroke, gastrointestinal bleeding/ulcers, kidney problems, and greater risk with long-term or high-dose use—it should not be used for Alzheimer’s prevention outside medical supervision or a trial.
The “known harms” mostly apply to higher-dose ibuprofen use. I think 100 to 200 mg per day, which would be low-dose, might be safe – especially the 100 mg range. And earlier in GPT-5.5-thinking’s analysis it is written:
Shorter use was not protective, and cumulative dose was not associated with lower risk, suggesting that duration rather than intensity drove the association.
So, you may not get any additional benefit from high-dose anyways, if there is any benefit at all.
…
I will say that I have noticed that low-dose ibuprofen improves my sleep quality and duration, which may be part of the benefit against Alzheimer’s risk (if there is any benefit at all). Acetaminophen does also, but it requires much higher dose to see much benefit. In fact, if I take 2 or 3 extra-strength Tylenol (which is a very bad thing to do, as it probably powerfully harms the liver; but I have done it), my sleep is usually very good.
I love that idea - and for science more broadly. It allows market economics to highlight areas of most promising research, and it allows impoverished researchers an opportunity to bet on (or against as a hedge) themselves and their research.
I used the choline/PEMT example precisely because I don’t think the Lancet commission would include it - even if the proof was there. Choline supplementation at population level may indeed not be productive (the association seems to be u-shaped) but may be strongly protective if an individual’s underlying genes cause a deficiency.
The Lancet commission would struggle to include choline in its list even if the evidence becomes very high for those with PEMT TT - Because the inclusion of a risk factor that depends heavily on individual genomics would require a fundamental shift in how the Commission calculates “Population Attributable Fraction”.
The one intervention I’d love to have a bet on as being effective though, is low dose lithium. It seems like the effect could be large. The associations from natural water supply, the hypothesized mechanisms and RCT pilot studies all point in the right direction and suggest a big potential affect size. Lithium alone could get us above your prediction - but I dread to imagine the policy debate about adding it to tap water!
NSAIDs appear on the Beers Criteria for potentially inappropriate medications in older adults.
Certainly, ibuprofen is not on my list for Alzheimer’s prevention.
GI bleeding—the risk rises steeply with age, and the elderly are more likely to bleed silently until they’re significantly anemic or hemodynamically unstable. Concurrent aspirin, anticoagulants, SSRIs, or corticosteroids compound this.
Cardiovascular — increased MI, stroke, and heart failure exacerbation. Ibuprofen also blunts the antiplatelet effect of low-dose aspirin if taken close together.
Hypertension — NSAIDs can raise BP and antagonize antihypertensive medications.
Researchers have shown for the first time that malfunctioning mitochondria — the cell’s energy generators — may directly cause cognitive decline in neurodegenerative diseases. By creating a new tool that temporarily boosts mitochondrial activity in the brain, scientists restored memory performance in mouse models of dementia. The discovery hints that energy failure inside neurons could happen before brain cells die, potentially offering a new target for future Alzheimer’s treatments.
I really like your list, And thought Id put it through Claude for a ranking and estimate of impact on dementia risk:
DEMENTIA RISK REDUCTION — RANKED INTERVENTIONS
RRR = estimated relative risk reduction · [cond] = conditional on subgroup · [e4] = APOE4-amplified
Evidence: A = RCT/strong prospective · B = cohort/large observational · C = small trials/mechanistic
Intervention Tier Est. RRR Evidence Key notes
── TIER 1 — Highest impact, strongest evidence ──
1 HSV antivirals (if HSV+) [cond] 1 60–90% B+ Tzeng cohort; Itzhaki mechanistic. HSV1+ only.
2 Sauna 4–7x/week 1 ~65% B+ Laukkanen/Kuopio prospective. HR ~0.35 vs. 1x/wk.
3 Vigorous cardio (Zone 4–5) + strength 1 35–45% A– VO2max top quintile ~35% RRR. Strength adds ~10% independently.
4 Hearing loss treatment [cond] 1 19–48% A– Largest PAF in Lancet 2020 (~8%). ACHIEVE RCT: 48% slower decline.
5 Alcohol abstinence [e4-amplified] 1 40–50% B+ Multiplicative interaction in e4. ~15–20% general population.
6 HRT — women, post-menopause [cond] 1 30–50% B+ Bioidentical estradiol, within 5yr of menopause.
7 GLP-1 agonists (semaglutide) 1 40–70% B+ Cleveland Clinic 1M+ retrospective. RCTs ongoing.
8 Sleep optimisation (7–8hr, N3) 1 25–35% A– Glymphatic amyloid clearance. U-shaped curve: <6hr and >9hr both elevated.
9 Diet: keto-Mediterranean intersection 1 35–53% B MIND diet 53% RRR. Keto adds neuronal ketone substrate.
10 Blood pressure control (midlife) 1 20–30% A SPRINT-MIND RCT. Target <120 systolic.
11 Sildenafil / tadalafil (PDE5i) 1 40–69% B Cleveland Clinic 7.2M-person database. cGMP → NO → cerebrovascular.
── TIER 2 — Moderate-high impact, reasonable evidence ──
12 Low-dose lithium 2 25–35% B Kessing Danish cohort; Forlenza MCI RCTs. GSK-3β → tau + amyloid. BDNF, autophagy.
13 Social engagement / cognitive reserve 2 20–25% B+ Lancet 2020 factor. Bilingualism, new skills, music.
14 B vitamins (methylated, high dose) [cond] 2 30–40% A– VITACOG: 53% reduced brain atrophy. MTHFR variants need 5–10x standard dose.
15 Air quality / PM2.5 avoidance 2 25–35% B ~30–40% elevated risk in high-exposure areas. HEPA filtration.
16 Omega-3 ≥2g/day [e4-amplified] 2 20–30% B e4: re-esterified TG + phospholipid form. Ethyl ester absorption impaired.
17 Green tea (3–4 cups EGCG) + coffee 2 25–35% B EGCG: amyloid inhibition, autophagy. Coffee ~27% RRR (meta-analyses).
18 Toxic metal elimination (Hg, Pb) [cond] 2 25–40% B Test first. Near-zero if unexposed. Chelate only if burden confirmed.
19 Homocysteine lowering 2 20–30% B+ Target Hcy <10 µmol/L. Delivered via B vitamins (#14).
20 Metformin 2 20–25% B– AMPK → mTOR suppression. TAME trial ongoing. May blunt exercise adaptation.
21 HBOT (males only) [cond] 2 20–30% B– Efrati 60-session protocol. ↑CBF, ↓senescent cells. Male-specific.
22 Testosterone optimisation (males) [cond] 2 15–30% B– Male HRT equivalent. Androgen receptors neuroprotective.
23 Fasting / TRE (independent of diet) 2 15–20% B– Autophagy window distinct from dietary ketosis. Circadian-aligned TRE.
── TIER 3 — Promising, emerging evidence ──
24 Rapamycin (higher intermittent dose) 3 20–40% C+ Animal evidence strong. e4: mTOR hyperactivation documented. PEARL trial ongoing.
25 Spermidine (wheat germ / supplemental) 3 15–25% C+ Kiechl/Graz cohort. EP300 inhibition → autophagy. Wirth RCT: memory improvement.
26 Plasmalogens 3 15–25% C+ Temporal cortex depletion precedes AD symptoms. Yanagisawa human trials.
27 Intranasal insulin [cond] 3 15–25% C+ Bypasses BBB and peripheral IR. High-value if insulin resistance present.
28 Melatonin (physiological 0.3–0.5mg) 3 15–20% C+ Anti-Aβ fibrillogenesis, metal chelation, glymphatic support.
29 Pioglitazone [cond] 3 15–20% C+ TOMORROW trial genotype-stratified subgroup. PPARγ → brain insulin resistance.
30 MCT C10 / exogenous ketones [e4 note] 3 10–20% C+ C10 → PGC-1α. Note: MCT response attenuated in e4.
31 CoQ10 (ubiquinol) + GG [e4-amplified] 3 10–20% C+ e4 Complex I/III impairment. GG as isoprenoid precursor.
32 NO synthesis pathway (nitrates, oral biome, MB) 3 10–20% C+ Dietary nitrates + avoid antiseptic mouthwash. MB: mitochondrial electron carrier.
33 40Hz multi-sensory stimulation + intranasal PBM 3 10–20% C Tsai/MIT gamma entrainment. Cognito Therapeutics trials. PBM: cytochrome c oxidase.
34 Lion’s mane (Hericium erinaceus) 3 10–20% C+ NGF + BDNF. Only dietary agent with adult neurogenesis mechanism. Mori MCI RCT.
35 NMN / NR (NAD+ precursors) 3 10–20% C+ SIRT1/3 → amyloid + tau biology. NAD+ decline drives multiple AD mechanisms.
36 Curcumin (Longvida / Theracurmin) 3 10–15% C+ UCLA/Small PET: reduced brain amyloid + tau. Standard form not absorbed.
37 Urolithin A (supplemental) 3 10–15% C+ Specific mitophagy. Gut conversion variable — Timeline Mitopure 500–1000mg bypasses this.
38 Berberine 3 10–15% C+ AMPK, mitophagy, gut-brain axis, anti-amyloid aggregation.
39 Trehalose 3 10–15% C TFEB autophagy. Bioavailability caveat: gut trehalase degrades oral form.
40 Selenium + magnesium L-threonate 3 8–12% C+ Se: GPx4 (ferroptosis). Mg-L-threonate: BBB-crossing form, ↑brain Mg2+.
I then asked Claude to estimate my dementia risk with some or all of these interventions at age 80, 90 and 100
DEMENTIA RISK PROJECTION
Male · APOE ε3/ε3 · Healthy baseline at 53 · UK population
Cumulative incidence if surviving to each age
Stack Age 80 Age 90 Age 100 ──────────────────────────────────────────────────────── Baseline (no interventions) ~11% ~26% ~45% Top 10 interventions ~6% ~13% ~23% Top 20 interventions ~4% ~10% ~17% Full stack (all 40) ~3% ~8% ~13%
Sub-additive pathway modelling · 25–35% publication bias discount applied
Realistic RRR: Top 10 ~50% · Top 20 ~62% · Full stack ~70%
Irreducible floor ~2–3% regardless of intervention intensity
Evidence is very far from perfect for all of these - but Im inclined to think this is also very far from BS especially in aggregate.
In aggregate, error bars should be reduced. And the cost side for most of these is relatively trivial (financial, time and side effect risk). I do 26/39 already and that covers most bases. It seems a sensible approach while we wait for Ai-led biology to solve this.
One extra point on rapamycin dosing - I recently tested a higher dose and hit the v. small mouth ulcer level at 9mg. Claude argues that i should use this dose quarterly because of its increased BBB penetration. Claude is guessing at serum sirolimus and cns penetration - but the logic is directionally sound. BBB penetration does seem to non-linearly correlate with serum levels. I’m inclined to go with a quarterly 9mg (normal dose 6mg) for brain-autophagy benefits - any thoughts?
Taken together, our data demonstrated that RJ could reduce cholesterol levels, regulate Aβ levels and enhance neuronal metabolic activities in AD rabbits, providing preclinical evidence that RJ treatment has the potential to protect neurons and prevent AD.
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.
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.
). Of course I would prefer to be wrong that we have to be realistic.
