Predicting Alzheimers & Dementia (and minimizing risk)

[adssx]

@DrFraser

I do give DHA to patients irrespective of family history or personal history of mental health disorders, and for the time being those with ApoE4’s. I’m waiting to be convinced that this isn’t sensible, and change my approach.

In RCTs only EPA helps for depression and EPA + DHA is neutral or detrimental.

In Mendelian randomization only EPA helps for depression: Omega-3 fatty acids and major depression: a Mendelian randomization study | Translational Psychiatry

Similarly for cardiovascular health only EPA seems to be helpful.

Same for cognition: Supplementation with oil rich in eicosapentaenoic acid, but not in docosahexaenoic acid, improves global cognitive function in healthy, young adults: results from randomized controlled trials 2021

ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial 2024: “Together these findings suggest that an EPA-dominant formula may provide some benefit in APOE-E4 carriers with no dementia and WMLs, and DHA-dominant formulas may benefit noncarriers of APOE-E4 with mild-to-moderate AD.”

ApoE4 carriers can’t transport supplemental DHA efficiently into the brain. Not matter the form (phospholipids or krill oil). And higher serum DHA is associated with MORE dementia.

So as of today the evidence is that supplementing with DHA in APOE4 carriers is useless at best. Detrimental at worst.

What’s the evidence in favor of DHA supplementation in ApoE4 carriers? It’s neither RCTs nor animal models nor Mendelian randomization nor association studies.

[adssx]

Ah also, there was the PreventE4 trial at the University of Southern California: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia

365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years.

The trial ended last year. The results were published:

The trial found that higher doses of omega-3s successfully penetrated into the brain but had no impact on cognition or hippocampal volume.

PreventE4: evaluating the role of omega-3 in cognitive health and Alzheimer’s...

So supplementing with DHA is useless for cognition.

[CronosTempi]

There is the common recommendaton that humans need marine omega-3. Of course there are other sources of long chain omega-3 than just from fish in the diet. What is often said, is that the short chain or the vegetable sources of n-3 are suboptimal, because many people don’t convert short chain to long chain very efficiently. Hence you need to take in long chain omega-3. But some people, often vegans, like to hold on to the n-3 and just trust that they convert enough. That’s one reason for the efforts by many to balance the n-6 FA with n-3, and arguments about what’s the optimal n-6/n-3 ratio. Flax seeds, chia seeds, walnuts etc. are consumed for the n-3. That was my approach for many years, although I do consume salmon and sardines 1-2 times a week, I did not supplement with fish oil. Eventually at some point I started supplementing, but limited myself to just EPA. What many people are not aware of though, is that if you supplement with DHA, depending on your genes, it has effects on the liver mechanism of DHA synthesis, so under any circumstances you may want to proceed with caution supplementing with DHA unless you know your SNPs well. Personally I’m staying away from supplementing with DHA. YMMV.

Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation

Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by...

[adssx]

This paper is crazy, thanks a lot for sharing!

One more reason not to supplement with DHA:

DHA is abundant in the brain where it regulates cell survival, neurogenesis, and neuroinflammation. DHA can be obtained from the diet or synthesized from alpha-linolenic acid (ALA; 18:3n-3) via a series of desaturation and elongation reactions occurring in the liver. Tracer studies suggest that dietary DHA can downregulate its own synthesis, but the mechanism remains undetermined and is the primary objective of this manuscript. First, we show by tracing 13C content (δ13C) of DHA via compound-specific isotope analysis, that following low dietary DHA, the brain receives DHA synthesized from ALA. We then show that dietary DHA increases mouse liver and serum EPA, which is dependant on ALA. Furthermore, by compound-specific isotope analysis we demonstrate that the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion as previously assumed. DHA feeding alone or with ALA lowered liver elongation of very long chain (ELOVL2, EPA elongation) enzyme activity despite no change in protein content. To further evaluate the role of ELOVL2, a liver-specific Elovl2 KO was generated showing that DHA feeding in the presence or absence of a functional liver ELOVL2 yields similar results. An enzyme competition assay for EPA elongation suggests both uncompetitive and noncompetitive inhibition by DHA depending on DHA levels. To translate our findings, we show that DHA supplementation in men and women increases EPA levels in a manner dependent on a SNP (rs953413) in the ELOVL2 gene. In conclusion, we identify a novel feedback inhibition pathway where dietary DHA downregulates its liver synthesis by inhibiting EPA elongation.

However, a significant effect (P < 0.05) of rs953413 was identified resulting in a 66% larger increase in plasma EPA levels for those individuals with the AA genotype (111 ± 18, nmol/ml ± SEM) compared to those with the GA or GG genotype (67 ± 11.1 nmol/ml).
Conversely, when DHA is absent in the diet, as would be common in vegans and those who do not consume fish, EPA elongation is not inhibited, and ALA can be used to synthesize DHA.
Beyond this, a literature is emerging suggesting that DHA may alter the effects from EPA. RCTs using mixed EPA/DHA supplements to reduce cardiovascular disease end points have been unsuccessful while two RCTs supplementing EPA alone reported cardiovascular benefits. Similar meta-analysis findings have been identified for major depression. Our mechanistic findings could help explain the contradictory RCT findings. EPA, when supplemented alone, is free for downstream conversion to DPAn-3 and its bioactive metabolites. However, when combined with DHA, EPA metabolism is inhibited and less available for potentially antiinflammatory metabolite production.

Conclusion: Supplement with DHA at your own risk.

[adssx]

@CronosTempi

you may want to proceed with caution supplementing with DHA unless you know your SNPs well

Your SNP changes the strength of the EPA increase after DHA supplementation, but no matter your SNP, DHA supplementation still downregulates its liver synthesis.

[Dr.Bart]

It has been 9 days, how did the daily ketone regimen work out for you?
Are you doing this with daily HIIT and KETO, or just regular healthy low glycemic diet ?

[CronosTempi]

Yes, mostly I pull out this paper when friends tell me that they are vegan/vegetarian, but supplement with fish/algae oil because they’re worried about not having enough long chain omega-3. Unless careful, they might make their conversion and synthesis worse. It’s safer to stick to EPA. But in general - and I guess this makes me an outlier - I think there is also the danger of too much long chain omega-3 FA. All the way back in my CR days on the list there was extensive discussion of the longevity downsides to having too much of these FA incorporated into the cell membranes, because they oxidise very easily and can be unstable; there was the view that excessive omega-3 consumption is a longevity negative. That’s to balance out the “more the better” mantra wrt. fishoil that’s prevalent today :).

[DrFraser]

This article shows incorporation and penetrance of Omega 3’s in ApoE4’s

I don’t think the article quoted on High Dose DHA in ApoE4 carriers answers any questions.

Let’s do it 20 years before likelihood of MCI or Dementia - then see actual outcomes. I don’t know the answer to this.

I however, don’t supplement only DHA, I agree with the comments on EPA, and generally use supplements that have a predominance of EPA. For example the NatureBell brand in double dose would be 480 mg of EPA, 320 mg of DHA and 800 mg of Phospholipids.

The statement of saying “had no impact on cognition” - well … I’m not interested in that - I’m interested in trajectory of decline in cognition. That is the key question.

[Dr.Bart]

That would be great to eliminate another supplement, Fish Oil is a big capsule too. I have 2 tbsp of Chia seeds and handful of nuts - mainly walnuts every day. On alternating days I will have pumpkin seeds, tempeh and can of sardines/other fish/shellfish- should be enough of Omega-3’s just from food alone. Dietary sources are typically superior to supplementation.

https://www.nationalgeographic.com/health/article/omega-3s-fish-oil-supplements

## Why fish oil supplements are not all they’re cracked up to be

Omega-3 properties are most powerful when they come directly from food—which offers a wider array of nutrients and more concentrated amounts of EPA, DHA, and ALA. There’s also a difference in the chemical structure of the fat in whole fish versus extracted fish oil, says Monti; and the manufacturing process can degrade the quality of nutrients in supplements and can even introduce worrisome contaminants.

An even more compelling reason to stick with food over omega-3 supplements? The purported cardiovascular benefits of fish oil supplements remain largely unproven in healthy people. “A lot of people became obsessed with fish oil about two decades back because there was initially some compelling data on improved heart health,” says Freeman, “but this data has since been largely refuted.”

Maybe the omega 3 fatty acid subject should be a separate thread.

[adssx]

@Dr.Bart

Maybe the omega 3 fatty acid subject should be a separate thread.

I wanted to call it “DHA sucks” but I chose a more politically correct title: 2g/day of DHA for 2 years has no impact on cognition or hippocampal volume

[adssx]

@DrFraser

This article shows incorporation and penetrance of Omega 3’s in ApoE4’s

Yes if taken intravenously. Is it still the case with oral supplementation?

@DrFraser

I however, don’t supplement only DHA, I agree with the comments on EPA, and generally use supplements that have a predominance of EPA. For example the NatureBell brand in double dose would be 480 mg of EPA, 320 mg of DHA and 800 mg of Phospholipids.

But what about the risk of DHA being detrimental as it self inhibits its biosynthesis and modifies the properties of EPA? Predicting Alzheimers & Dementia (and minimizing risk) - #570 by adssx

@DrFraser

The statement of saying “had no impact on cognition” - well … I’m not interested in that - I’m interested in trajectory of decline in cognition. That is the key question.

That’s true but there’s zero evidence that DHA might positively affect the trajectory.

[Satchel]

I will dig up the paper- but a Danish study showed that anyone who took a “cyclovir” type drug for 2 weeks, at any point in their lifetime had a significant reduction in dementia and Alzheimer’s.

[AinmRapaNui]

Anecdotal comment:
I took Omega-3s for years.
My sleep just got worse and worse, my anxiety more and more horrible.
After reading some of the work of Dr. Peat, I stopped all omega-3 supps, and stopped eating salmon (I have cod instead, along with ground beef).
I now feel a little better every day.
My sleep is recovering, after years of suffering.
You might want to read the most important Peat article that I ever read:

The Great Fish Oil Experiment

Also:
https://lowtoxinforum.com/threads/higher-omega-3-omega-6-ratio-may-damage-the-brain-irreversibly.6760/

[Neo]

@adssx

In Mendelian randomization only EPA helps for depression: Omega-3 fatty acids and major depression: a Mendelian randomization study | Translational Psychiatry

Same for cardiovascular health.

Can you share more on that

@adssx and @CronosTempi do you have recommendations for a high quality EPA only supplement?

[Neo]

@Dr.Bart

Omega-3 properties are most powerful when they come directly from food

@adssx @CronosTempi

What are your thoughts on that?

If the main reason a person adds fish to an otherwise vegan diet has been for the fish oils/omega 3s, would you think that is better than supplementing just EPA or that giving up on the fish and just supplementing EPA might be the best?

[59vw]

Yeah the 50 yo recommendation for Shingrix has to do with the increasing risk of developing shingles as immunity wanes as you get older. I think as long as you get Shingrix before you develop actual shingles that you are probably good but there is some line of thought that there may be some sub-clinical inflammation going on prior to developing all out shingles and that receiving the Shingrix vaccine may reduce that and thus reduce the risk of AD. This is speculation but it is one of those theories that makes a lot of sense and if you are ApoE 4/4 I think I’d err on the side of caution and get the Shingrix booster now.

Fair warning though… I’m 60 and got the first dose (of two spaced 2-6 months apart) a year ago and my reaction was significant enough that I didn’t go back for dose 2! I kind of wish I had and I’m pretty sure I can get dose 2 anytime so once I’ve forgotten the headache, body aches, and chills I’ll go back for #2. Probably since I had such a significant reaction I had pretty good immunity already.

[medaura]

I’m sorry to have to put it this bluntly because I value your contributions a great deal but your take here is so sloppy I’m a bit shocked.

https://www.medpagetoday.com/meetingcoverage/ctad/112713#:~:text=High-dose%20supplements%20of%20docosahexaenoic,has%20been%20inconsistent%2C%20he%20noted.

High-dose supplements of docosahexaenoic acid (DHA), an omega-3 fatty acid, penetrated the brain in both APOE4 carriers and non-carriers before dementia onset, the placebo-controlled PreventE4 trial showed.

The treatment did not influence hippocampal volume, said Hussein Yassine, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles. However, increases in brain DHA in both the treatment and placebo arms were associated with better cognitive measures in APOE4 carriers, Yassine reported at the Clinical Trials on Alzheimer’s Diseaseopens in a new tab or window annual meeting in Madrid.

“Omega-3s are good for the APOE4 brain when started before dementia symptoms,” Yassine told MedPage Today. “This is different in dementia, when APOE4 carriers have a lower increase in brain DHA after supplementation than non-carriers,” he pointed out.

“What’s novel about these findings is that the benefit was greater for those with Alzheimer’s genetic risk,” he added.

Lower blood omega-3 levels have been correlated with worse cognitive function in several observational cohorts, particularly among APOE4carriers, but the effect of omega-3 supplementation on cognitive outcomes in clinical trials has been inconsistent, he noted.

“In general, very few studies have examined brain DHA delivery as a metric for treatment efficacy,” Yassine said.

DHA is mostly obtained from fatty fish consumption. It’s the predominant omega-3 in the brain by weight and comprises up to 40% of fatty acids in gray matter.

Earlier studies showed that the brains of young (age 35) cognitively normal APOE4 carriers were more dependent on circulating DHAopens in a new tab or window than non-APOE4 brains.

“This means that the APOE4 brain is taking more DHA from plasma into the brain for its normal biological processes,” Yassine said. “It consumes more DHA, like a specific engine that requires a specific oil to function.”

Since plasma DHA levels are largely determined by dietary intake, this finding implies vulnerability of APOE4 carriers to a low DHA diet, he noted.

PreventE4opens in a new tab or window was a double-blind, single-center trial of cognitively unimpaired individuals with at least one vascular dementia risk factor and limited seafood consumption (DHA intake less than 200 mg/day). People who used omega-3 supplements in the last 3 months were excluded. By design, half the study population had at least one APOE4allele.

It shows the opposite of what you claimed! Even if there was no difference to cognition among the study’s arms, it wouldn’t have proven anything as 6 months (or was it 2 years?) isn’t enough time to create a delta in outcomes. What’s important here is that it proves dietary supplementation of DHA DOES make it up the apoE4 carrier’s brain. This is news to me and maybe I’m wasting money and taking extra pills I don’t have to by opting for the phospholipid form. Doesn’t affect hippocampus volume but so what? It actually does seem to make a difference to cognition.

Anyway, I don’t mean to be rude. You’re as good a contributor as they get. Just surprising to me how you could interpret something for its obvious opposite.

[Shady]

I’ve enjoyed the ketone supplement trial. I’m using DeltaG ketone monoester. I’m doing 5-10g each AM depending on my schedule that day. I will say that mental clarity/processing is improved compared to baseline, but not to the same degree as HIIT + Ketones. Those days are exceptional. Noticeable appetite suppression that wears off by evening. No side effects. No effect on sleep (always hopeful something improves that). I did hit my lowest resting heart rate last week (48), but not sure the ketones played a role in that. May just be improving cardio fitness from my workouts.

Overall, I plan to keep with it for a while. Will report back if anything else noticeable.

[CronosTempi]

A doctor whom I asked recommended Igennus Pharmepa Restore, so that’s the EPA I take. BUT, I take extremely modest amount: 500mg three days a week, on days I don’t eat fish - so I have some fish oil exposure four-five days a week counting the fish. But I only supplement small amounts of EPA, because I’m only looking to prevent frank deficiencies - I am unconvinced that the massive recommendations 2-4g a day are beneficial at all for me. Wrt. fish, the EPA/DHA content is not really a big consideration for me. I consume salmon/sardines 1-2 times a week based on epidemiological evidence of health outcomes. Why exactly such fish are healthy I’m agnostic on, and suspect that their EPA/DHA content is only a tiny part of it.

[AnUser]

AlmegaPL seem interesting as a plant-based option (though niche product, probably small company). Probably won’t have in expectation much of a difference with fish oil with regards to health (except mechanistic speculation).

The daily intake of LCn-3 PUFA in AlmegaPL® (250 mg/day), while consistent with the promotion of cardiovascular health in a generally healthy population (26), is well below the intake levels (2000–4000 mg/day) recommended to treat CVD in diseased participants (23). Thus, AlmegaPL® is intended for healthy adults seeking cardiometabolic support rather than for treatment of CVD. The impact of LCn-3 PUFA intake on the TG levels follows a dose-response relationship, even at relatively low supplementation levels (200–500 mg/day), where the TG decrease is estimated at 3.1–7.2% relative to baseline (27). In the present study, AlmegaPL® decreased TG levels by 14.2% (−0.23 ± 0.64 mmol/L; p < 0.001) after 6 months (primary outcome) of supplementation, a response equivalent to 4-times the DHA + EPA dose reported for other LCn-3 PUFA sources (27). This suggests that LCn-3 PUFAs alone might not explain the high response obtained with AlmegaPL®, and some other factors might be at play. While EPA-only composition outperformed DHA + EPA in terms of decreasing MACE (8), there is no consensus on whether the EPA-only composition truly increases the LC-3 PUFA capacity to lower TG (28, 29). In turn, the polar form (glycolipids and phospholipids) to which the EPA is conjugated in AlmegaPL® may partially explain the greater reductions observed for TG.

Study suggested EPA decreases LDL-C, while DHA doesn’t, as well, IIRC, and a trend towards CRP decrease.

Consistent with our previous study (14) and with EPA-only formulations in general, LDL remains unchanged, ultimately resulting in significant decreases in TC (5.0%; −0.26 ± 0.98 mmol/L; p < 0.001) and non-HDL-C (5.5%), both of which are well-characterized risk factors for CVD. According to Varvo (33), RC, but not LDL, causes low grade inflammation, which explains why the inflammatory marker hs-CRP (high-sensitivity C-reactive protein) decreased by 30.2% (−0.92 ± 5.85 mg/L), albeit not significantly (p = 0.146). The lack of significance might be explained by the non-specific nature of the acute-phase hs-CRP response. This response can be dramatically triggered by many disorders unrelated to cardiovascular disease (e.g., infection) and may interfere with the interpretation of results in numerous CVD studies (34).

Omega-3 eicosapentaenoic polar-lipid rich extract from microalgae Nannochloropsis decreases plasma triglycerides and cholesterol in a real-world normolipidemic supplement consumer population 2024

Supplement to Support Heart Health | iwi life