#588

I have a hypothesis that it’s better to purchase things and use that which is high volume to reduce risk of black swans or increase detection of them, and study said first time this algae used 2014, who knows. But I haven’t looked at the previous data to try and test to do a rootclaim (http://rootclaim.com/) type analysis (w/ help of e.g chatgpt currently). So it’s mostly feeling.

Besides consistently applying such a heuristic would not lead to use novel interventions, I guess, so I might be wrong.

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#589

As long as it’s not worse that seems good to me

Interesting that say

Fish are certainly the most famous source of omega-3 EPA and DHA, but guess what? Fish don’t make it themselves–they borrow it from algae! In addition to being able to “cut out the middle fish,” many consumers are making conscious choices about what they eat, whether it’s from an environmental standpoint, or concern over microplastics, mercury, and lead in ocean fish. In addition, since fish obtain their EPA and DHA omega-3 from algae, farmed fish does not contain much of these essential fats. Be sure that your brain, heart, eyes, and joints get what they need by adding iwi life to your supplement routine.

@DrFraser saw you liked krill oil due to absorption benefits, this company says the below (I have not had time to verify it:

absorption matters

Human clinical science performed by an independent 3rd-party lab (KAGAN ET AL) demonstrates that Omega-3 from AlmegaPL* offers 1.7x the absorption rate of fish oil, krill, and other algae oils. This confirms the enhanced bioavailability of our unique algae-sourced Omega-3.

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#590

I think that should be part of the framework

But married with other things

For instance here we might want to weigh grown algee likely not having the same risks of

concern over microplastics, mercury, and lead in ocean fish

How to weigh those two different arguments things though I don’t know?

The fact that they are doing trials seems more legit than the average company so that adds to the plus side

And same with the NSF and claimed third party testing

Two key questions I have is if their dose might be too low and if the other omegas and chlorophyll that are parts of the mix are net good

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#591

I personally use NOW Ultra Omega-3. It has a 2:1 ratio of EPA to DHA and when I test the capsules, they are not rancid. NOW also has a high threshold for quality, so I believe that heavy metals and other toxins should be minimal. I take 2 1g capsules daily.

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#592

Thanks @medaura for sharing this article that gives more details about the study, I only found Yassine’s video before. I still think the video is more informative:

Yassine says at 3 min that a higher level of Omega 3 in the omega 3 arm AND in placebo arm was associated with better cognition and therefore we need to determine what determines higher levels of omega 3 if it’s not supplementation. For instance, exercise might help. He concludes at 4:30min:

But importantly, just taking the supplement without changing anything else in your lifestyle was not associated with any improved cognition in this trial.

This is the principal investigator’s conclusion. The conclusion of someone who highly believed in the potential of DHA for cognition and spent years of his life studying it. If we don’t use a large high-quality RCT to make decisions for our health, what do we do?

  1. It doesn’t show the opposite, in my post I wrote their conclusion: “The trial found that higher doses of omega-3s successfully penetrated into the brain but had no impact on cognition or hippocampal volume.”
  2. 2 years is enough, the trial had a large size to detect a 0.5 SD effect size: 2g/day of DHA for 2 years has no impact on cognition or hippocampal volume - #8 by adssx
  3. Besides cognition, they looked at hippocampus volume. As noted by @CronosTempi, daily rapamycin increased hippocampal volume in 4 weeks and exercise in 1 year so:

Bottom line, it appears that increasing the hippocampal volume can be accomplished in relatively little time - as little as 4 weeks. Not to do so at all in 2 years represents catastrophic failure and giving it even more time when 2 years was not enough is unlikely to suddenly start enlarging.

Also, what do you say about DHA supplementation inhibiting its biosynthesis? Predicting Alzheimers & Dementia (and minimizing risk) - #570 by adssx

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#593

More on EPA vs DHA for cardiovascular health:

My conclusion: only EPA has proven cardiovascular benefits (and still there it’s not super obvious and there’s some controversy).

High-quality EPA only: Vascepa is a prescription drug, EPA only, that’s the one used in clinical trials that showed benefit. Pharma-grade quality + proven benefits = the best option. The second best for those who cannot buy Vascepa (it’s expensive and not available everywhere) is probably Carlson, Elite EPA Gems, 1,000 mg, 120 Soft Gels.

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#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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