#594

As a reminder, fish oil (EPA + DHA) failed in the ITP:

On the other hand, a recent Chinese paper found that for EPA-only, Omega-3 PUFAs slow organ aging through promoting energy metabolism 2024:

We found EPA intervention improves the levels of other beneficial PUFAs, like DPA in serum and kidney. And there was no significant difference in DHA level (Fig. 3P). Interestingly, the level of Omega-6 PUFAs were significantly lowered by EPA supplementation, as well as the ratio of Omega-6 to Omega-3 PUFAs (Fig. 3Q, R). These results indicate EPA supplementation could reprogram energy metabolism and boost FAO to protect against aging process.

I really don’t understand the case for DHA supplementation. The evidence is so weak compared to other things (SGTL2i, GLP-1RAs, ezetimibe, telmisartan, amlodipine, rapamycin, vitamin B12, etc.) that it seems overrated at best or totally unproven pseudoscience at worst.

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#595

But extrapolated from where? What RCT to extrapolate from, or 20 year out with a MR study, do we see an effect?

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#596

Interestingly, Yassine, the PI behind the failed PreventE4 trial wrote this paper last year (before the PreventE4 results were known): Designing Newer Omega-3 Supplementation Trials for Cognitive Outcomes: A Systematic Review Guided Analysis 2024.

In his words (those of a high believer in omega 3 supplementation at least when he started the PreventE4 trial…):

Conclusions: We recommend that newer n-3 PUFA supplement trials targeting AD prevention be personalized. For the general population, the null hypothesis appears to be correct, and future interventions are needed to identify and test dietary patterns that include PUFA-rich food rather than supplements.

Given that the majority of clinical trials involving n-3 PUFA supplements and cognition reported null findings, we must consider the possibility that the null hypothesis is correct. That is, there is no true difference between n-3 PUFA supplements and placebo in AD prevention or treatment in the older general population. […] However, it is plausible that these clinical trial interventions were not long enough to find a true effect, given that the prodromal phase of AD can last 10–20 years. […] We propose that carefully selected populations may benefit from n-3 PUFA supplementation and present some of the factors that can help define these individuals for personalized intervention with either an n-3 PUFA supplement or an n-3 PUFA dietary pattern.
This association between DHA intake and dementia outcomes is more evident when comparing individuals who do not consume fatty fish to those who consume one or two servings. However, the association between baseline n-3 PUFA-enriched dietary intake and dementia differs according to the population characteristics. Some vegetarian and vegan populations that do not consume red meat, chicken, or fish do not have an increased risk of dementia despite lower n-3 PUFA levels, suggesting compensation for lower n-3 PUFA intake. It is plausible that such populations have lower vascular risk factors and less vascular dementia; however, further research is needed. We recommend that future trials select participants based on low baseline n-3 PUFA levels in the context of a Western dietary lifestyle.
Overall, n-3 PUFA doses of less than 1 g/day are not likely to significantly increase brain levels within a short period of time of supplementation. In the DHA pilot trial, we observed a 28% increase in CSF DHA levels after 2 g of algal DHA per day over 6 months compared with placebo, despite a > 200% increase in plasma DHA levels. These findings suggest that lower doses (<1 g of DHA per day) are likely to be associated with lower brain DHA delivery. Dementia prevention trials using omega-3 supplementation doses equal to or lower than 1 g/day may have reduced brain effects, particularly in APOE4 carriers owing to lower brain uptake or greater brain consumption […] The clinical evidence regarding whether DHA or EPA in triglyceride or phospholipid form is superior remains inconclusive.
N-3 PUFAs, particularly DHA, have a long half-life in the brain of around 2.5 years, and their effects on brain structure may take time to manifest. Therefore, long-term interventions with lower doses of omega-3 fatty acids may not be sufficient to produce significant changes in brain levels or structural changes such as brain volume. […] Overall, a supplementation duration longer than 6 months is recommended.
Among n-3 PUFAs, EPA intake appears to be more advantageous than DHA in reducing “brain effort” relative to cognitive performance.
All participants in PreventE4 receive high dose vitamin B supplementation to eliminate any confounding effects of high homocysteine levels on the outcomes. The trial is expected to be reported in 2025.

So, according to Yassine (and that was before he got the results of his PreventE4 trial!), most likely, “there is no true difference between n-3 PUFA supplements and placebo in AD prevention or treatment in the older general population”. But there might be some benefits of high-dose (>1g/day) supplementation in people with a Western diet that don’t eat fish (but not vegans who eat healthy) and new trials are necessary to prove it. He adds: “Combination interventions, such as multi-domain, multi-nutrient, or dietary patterns, are likely more effective than n-3 PUFA supplementation alone.”

It seems that Yassine now shifted his work on cPLA2 inhibitors that can increase brain omega-3 levels: Novel mechanisms to enhance omega-3 brain metabolism with APOE4 2023

Is there any strong paper in favor of DHA supplementation for dementia prevention given the massive amount of evidence showing that it is useless?

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#597

Thanks Adssx. The thing I was asking about is the

In Mendelian randomization only EPA helps

part for cardiovascular health. That for me would be a very compelling piece of evidence, since it will help understand very long term exposure to higher EPA

Can you point to the underlying study/ies for your statement on MR showing EPA helping with CVD

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#598

Sorry, my message wasn’t clear. I edited it. I meant that for CVD, only EPA was helpful (but even that is controversial).

MR I’ve just found:

My understanding so far (and I’d love to be wrong!) is that DHA is not beneficial for CVD, mental health or cognition (and that it might even be detrimental), while EPA (with a rather weak level of evidence) might be beneficial but rather safe so it might be a good bet (although it probably comes after many other interventions).

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#599

One last MR for Alzheimer’s disease to once and for all conclude that omega 3 is useless: Investigating the Genetic Influence of Omega-3 Fatty Acids on Alzheimer’s Disease Risk Through Mendelian Randomization 2024

Results: The analysis did not reveal any significant causal effects of genetically predicted n-3 FA levels on the risk of developing AD. The odds ratios (OR) and 95% confidence intervals (CI) for a one standard deviation increase in serum levels of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were 0.96 (95% CI: 0.88, 1.06), 1.02 (95%CI: 0.99, 1.06), 1.03 (95% CI: 0.97, 1.09), and 1.00 ( 95% CI: 0.81, 1.26), respectively. These findings remained consistent when adjusting for the presence of n-6 FAs in the MVMR analysis, suggesting no direct genetic influence of n-3 FAs on AD risk within the bounds of this study.
Conclusions: Our findings indicate no genetic evidence to suggest a causal relationship between n-3 FA levels and the risk of AD. These results may clarify the context of conflicting evidence from observational studies and randomized controlled trials.

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2g/day of DHA for 2 years has no impact on cognition or hippocampal volume
#600

@adssx Do you think this is the case for whole fish too?

#601

I don’t know at all. I haven’t checked. Maybe in food it’s better absorbed? Maybe it’s in a different form? Maybe there’s something else in fish other than just EPA and DHA that is beneficial? But what about heavy metals and other pollutants? :man_shrugging: I like fish so, I try to eat some once or twice a week, for taste rather than health :smiley:

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#602

The tricky thing about fish versus omega-3 capsules is that somebody eating fish is eating less of something else. You can run a study where you hold diet constant and add omega-3 capsules. When you do an observational study and look at fish consumption you are by construction not keeping diet constant.

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#603

@adssx so should we care about omega-3 index at all? Seems like no.

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#604

Maybe if your omega 3 index is severely low then you should eat more fish or supplement with EPA? Or maybe the omega 3 index is totally irrelevant? I don’t know but what I know is that DHA supplementation is useless if not detrimental for mostly everything. For EPA: TBD.

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#605

On more MR: Risk of Alzheimer’s disease and genetically predicted levels of 1400 plasma metabolites: a Mendelian randomization study 2024

“The detailed names of the 1,400 metabolites and metabolite ratios are given in Supplementary Table S1.”

Among other things, they looked at:

  • “Docosahexaenoate DHA; 22:6n3 levels”
  • “Eicosapentaenoate (EPA; 20:5n3) levels”

And they found no association with AD.

#606

But shouldn’t we expect to see at least some improvements in certain subgroups or a trend towards improved cognition if DHA was any good at all?

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#607

For those not yet convinced, one more MR, by the great Sara Hägg: Polyunsaturated fatty acids and risk of Alzheimer’s disease: a Mendelian randomization study 2019

None of the genetically predicted PUFAs was significantly associated with AD risk; odds ratios (95% confidence interval) per 1 SD increase in PUFA levels were 0.98 (0.93, 1.03) for linoleic acid, 1.01 (0.98, 1.05) for arachidonic acid, 0.96 (0.88, 1.06) for alpha-linolenic acid, 1.03 (0.93, 1.13) for eicosapentaenoic acid, 1.03 (0.97, 1.09) for docosapentaenoic acid, and 1.01 (0.81, 1.25) for docosahexaenoic acid.
This study did not support the hypothesis that PUFAs decrease AD risk.

And @Neo one more MR for CVD: Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk: analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants 2022

Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus.
We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses.

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#608

The issue goes beyond supplementing with DHA only. Any kind of DHA supplementation seems detrimental, as dietary DHA downregulates DHA biosynthesis, inhibits EPA elongation, and blunts the benefits of EPA: Predicting Alzheimers & Dementia (and minimizing risk) - #569 by CronosTempi

This is confirmed by: Higher docosahexaenoic acid levels lower the protective impact of eicosapentaenoic acid on long-term major cardiovascular events 2023

Conclusions: Higher levels of EPA, but not DHA, are associated with a lower risk of MACE. When combined with EPA, higher DHA blunts the benefit of EPA and is associated with a higher risk of MACE in the presence of low EPA. These findings can help explain the discrepant results of EPA-only and EPA/DHA mixed clinical supplementation trials.

Paper from Stanford + University of California San Diego + University of Utah.

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Dr. Rhonda Patrick - Omega 3 is The Only Supplement that ACTUALLY Increases Lifespan
#609

Which supplements would you use for EPA? @adssx

#610

Those: Predicting Alzheimers & Dementia (and minimizing risk) - #593 by adssx

But I stopped taking EPA for neuroprotection as it seems of low value. (There was also one low-quality Mendelian randomization study that found a statistically non-significant increase in PD risk with EPA so I prefer to err on the side of caution…)

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#612

But the study you linked said it doesn’t:

Study Results

There was no beneficial effect of treatment with omega-3 PUFAs compared to placebo; the rate of transition over 2 years did not differ between treatment arms nor was there a difference in change in symptom severity after 6-month treatment. Dropout rates and serious adverse events were similar across the groups.

Conclusions

This is the third study that fails to replicate the original finding on the protective effect of omega-3 PUFAs in UHR subjects for transition to psychosis. The accumulating evidence therefore suggests that omega-3 PUFAs do not reduce transition rates to psychosis in those at increased risk at 2 years follow-up.

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#613

Yet another total lose for the overrated omega 3.

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#614

I am wondering if an even higher EPA:DHA ratio would make a difference or just skip the fish oil altogether?

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