Omega-3 Supplements May Increase Risk of Cognitive Decline, Scientists Warn

#101

Good question. I honestly don’t have a good reason, other than my chosen supplement contains both! The JACC study is definitely very interesting.

I can look around and see whether I can find a good quality EPA-only supplement. If I can, then I would probably move to that.

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#102

Since you shared quite a few papers and going through them one by one would be too time-consuming, I’ll just focus my response on the most recent study about Omega-3 supplements accelerating cognitive decline in older adults.

That study analyzed the ANDI dataset. Interestingly, using that exact same data, a 2023 research team came to the opposite conclusion—that it actually reduces the risk of Alzheimer’s by 64%. Why would the same data yield different results? Because the studies had completely different endpoints: one looked at the risk of developing Alzheimer’s, while the other measured the rate of cognitive decline. So, that explains that.

Also, I want to apologize for just copy-pasting the papers the AI generated for me earlier without reading them carefully. I was just being lazy. Honestly, I’ve spent years constantly updating my evidence base as new research comes out, so I think I’ve developed a subconscious resistance to doing deep-dive analyses all over again.

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#103

If you want to stay with Nordic Naturals, they don’t offer EPA-only unfortunately but they have an EPA-strong one which would give you half your current DHA for a bit more EPA: EPA - Omega-3 Fish Oils | Nordic Naturals

However… before doing so… have a look at this Harvard / CUNY preprint from last month: Causal role of EPA on ischemic heart disease, triglyceride rich lipoproteins and related traits: A two-sample Mendelian randomization analysis 2026

RESULTS Using IVW, EPA was associated with higher odds of IHD (OR=1.05; 95% CI=1.00, 1.10), but the CI included the null value. The WM estimate was similar, and the MR-Egger estimate was closer to the null (OR=1.01; 95% CI: 0.90, 1.11). EPA was associated with lower serum TG and lower large to small very low-density lipoprotein (VLDL) particle concentrations, but with increases in very small VLDL, intermediate density lipoproteins, and low-density lipoproteins. Although the distribution changed from larger to smaller TRL, there was no change in apolipoprotein B. EPA was also associated with increases in very large to medium high-density lipoprotein (HDL) particles and no change in small HDL, consistent with an increase in apolipoprotein A-I. EPA was also associated with increases in both remnant cholesterol and total serum cholesterol.

DISCUSSION This study suggests that EPA may not have a beneficial effect on IHD in the general population of European ancestry. Rather, EPA appears to remodel TRL, possibly through lipolysis of large particles without full clearance of the resulting smaller particles, and this may have mixed implications for cardiovascular disease risk. A cardiovascular outcome trial of EPA monotherapy in a general population that collects lipid/lipoprotein subfractions would be needed to confirm these findings.

If I understand correctly, the EPA may lower triglyceride levels by breaking large particles into smaller ones.

So:

  • If you have high TG, then this paper confirms EPA is useful (and it confirms the REDUCE-IT results).
  • But if your TG is already normal, the small TG-lowering brought by EPA supplementation is clinically irrelevant, and on the other hand, it comes with higher remnant/IDL/LDL particles.

To me, as someone with normal TG, this seems to be a net negative. It might explain the discordant results regarding EPA. Of course, it’s a preprint, and it’s an MR but the case for EPA supplementation in normal TG was already weak, it’s getting weaker…

What do you think? Poke @A_User @CronosTempi @DeStrider @Davin8r

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#104

Going through the shitty papers you lazily copy-pasted was also time-consuming for me. You’re wasting everyone’s time. Thanks at least for apologizing…

Anyway, I assume the 2023 paper you mentioned is The Relationship of Omega-3 Fatty Acids with Dementia and Cognitive Decline: Evidence from Prospective Cohort Studies of Supplementation, Dietary Intake, and Blood Markers. They found a 64% lower risk of AD (HR 0.36). That’s most likely over-optimistic bullshit, as RCTs would have captured such a massive protective effect. Still, the contradiction between the 2023 and 2026 papers shows the weakness of observational studies. They’re highly model-dependent.

#105

I do my best to keep triglycerides and ApoB and LDL as low as possible. My mother has always had low LDL and ApoB yet her triglycerides are through the roof. This caused her to have both a heart attack and stroke. She also had high blood pressure.

#106

Got it, so you’re in the high TG population for which EPA supplementation definitely makes sense and is a clear net positive. Makes sense to supplement then!

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#107

@Cole

lol he won’t pay any attention to anything that doesn’t fit his anti DHA agenda. From a very simplistic point of view, why DHA?

  1. Can you find me a fish with only EPA in it?
  2. Is my brain naturally high in DHA? Is my body efficient at making DHA?
  3. numerous studies of various types showing potential benefit to DHA.
  4. Other evidence shows potentially no benefit but doesn’t seem to show harm.
  5. Mouse study and recent ADNI study show harm. Shortcomings of these studies have been pointed out but not acknowledged by the anti DHA side of this argument.
  6. DHA may be associated with depression. HR ~1.1. That HR isn’t impressive. Numerous other studies show benefit to fish oil on depression so perhaps another way to argue that isolated DHA is not optimal. GLP1s are also linked to depression and anhedonia in some studies so we should campaign for everyone to quit those as well?
  7. Most fatty fish contain more DHA than EPA. Often ~2:1. How do we reconcile the ratio in nature with the theory DHA causes harm?

I’m not arguing DHA is some cure all. I’m arguing that fish oil is unlikely to be detrimental based on the totality of evidence and likely provides some benefit in the long term.

99% of the supplements we take have less data than fish oil. I find this conversation somewhat comical. Throw the fish oil out but keep taking Rapa, spermidine, Vit D, etc. confirmation bias is strong.

Mayo Clinic published a meta analysis showing reduction in CV mortality with omega-3. I trained there. I have full faith in the institution. Until we have similar data showing harm I’ll keep with my daily fish oil rather than jump on and off based on mouse studies and an ADNI study with poor protocols.

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#108

I think it is always wise to keep an open mind.

Yes, fish oil has been studied more than anything else. And is no longer recommended for primary disease prevention.

I am no expert on the history of all this. But the AHA changed guidance in 2017 away from recommending fish oil to at risk populations outside of high triglycerides.

So studied a lot and now not recommended - at least from a CV perspective.

That is a lot different than something that has never been recommended. Takes a lot for organizations to change their mind. When was this Mayo study published?

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#109

I respect your comment. At the same time other things that aren’t recommended for primary prevention in healthy ppl - statins, zetia, pcsk9 inhibitors, Acarbose, GLP1, SGLT2, Rapa, vit D, etc. if anyone here is basing their protocol purely on medical guidelines I respect them. That said, I think the majority of us here are of the idea that medical guidelines may be great on a population basis for the general population but may not be optimal for each individual to maximize longevity and health.

#110

Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials

Results

A total of 40 studies with a combined 135,267 participants were included. Supplementation was associated with reduced risk of MI (relative risk [RR], 0.87; 95% CI, 0.80 to 0.96), high certainty number needed to treat (NNT) of 272; CHD events (RR, 0.90; 95% CI, 0.84 to 0.97), high certainty NNT of 192; fatal MI (RR, 0.65; 95% CI, 0.46 to 0.91]), moderate certainty NNT = 128; and CHD mortality (RR, 0.91; 95% CI, 0.85 to 0.98), low certainty NNT = 431, but not CVD events (RR, 0.95; 95% CI, 0.90 to 1.00). The effect is dose dependent for CVD events and MI.

Conclusion

Cardiovascular disease remains the leading cause of death worldwide. Supplementation with EPA and DHA is an effective lifestyle strategy for CVD prevention, and the protective effect probably increases with dosage.

#111

Just (another) quick thought on eating fish to get round the omega-3 supplement uncertainty.

For anyone who doesn’t like the taste /texture 9f oily fish - I heartily recommend salmon cakes. Both the texture and taste are/can be disguised. My daughter eats sushi but doesn’t like cooked salmon - this was the answer to getting her intake up to 2 portions a week…

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#112

Please try to elevate the debate, @Shady; otherwise, there’s Reddit for you.

Yes, those were the hypotheses behind DHA supplementation. They were legit. But they failed. So we need to look at the evidence and move on.

I posted evidence of harm, including in humans:

Of course, the ADNI is a longitudinal study, so it’s low-quality evidence. But so far, most of the pro-DHA argument relies either on mechanistic hypotheses (as yours above) or on longitudinal studies. So this is the same type of evidence.

It’s not an association, it’s causal, it’s a 5.3-year RCT with 18k participants. 1.13 is not small, given that most RCTs for depression usually find benefits. GLP-1RAs have extraordinarily strong and proven benefits, so the depression risk is worth it in the vast majority of people (unless at high risk of depression and/or already super healthy). There’s always a trade-off for any intervention.

  1. Dosis sola facit venenum:
  2. The benefits seen with fish consumption might be confounding (income, education, healthy user bias, etc.).
  3. The benefits of fish consumption might come from what you are NOT eating, rather than what you are eating. Most likely red/processed meat. So the net effect of fish can be good even if one isolated component is mixed/detrimental.
  4. Something else in fish, other than omega 3, might be highly beneficial and counteract detriments.
  5. Nature is not an optimization argument.
  6. The form might be different. Maybe most DHA supplements, including those used in studies, are in practice of low quality, or oxidized, or whatever. Or maybe you body can very well leverage DHA from fish but less so from supplements. Maybe it has to be combined with something else. Maybe it needs to be hot. Maybe whatever, who knows?! (see below)

Then what’s your answer to the 11 papers I posted above?

Of course 99% of supplements are BS. At the end what matters: cholesterol lowering (statins, ezetimibe, PCSK9i), BP control (telmisartan, amlodipine), glycemic control (GLP-1RA, SGLT2i), kidney (all before) + vitamins & iron if deficient. The rest is often largely BS. Rapamycin might be one of the few exceptions. The evidence in favor of rapamycin looks better to me than for DHA.

Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials

“Published online September 17, 2020” “which covers all randomized control trials with EPA/DHA interventions and cardiovascular outcomes published before August 2019.” => 7 years is a long time! This is old. Still, they wrote:

EPA Compared With EPA+DHA
It has been observed that DHA supplementation can increase low-density lipoprotein cholesterol (LDL-C), and some researchers believe that omega-3 supplementation would be safer if it consisted primarily of EPA.22 But LDL-C is an imperfect marker of CVD risk, and although DHA increases LDL-C, it does not change apolipoprotein B.23-25 This is consistent with shifting LDL particles to a larger, less atherogenic profile.
There is a lack of data to address this question. Because there is the belief that EPA is better for CVD prevention, most of the information available for larger dosages has been obtained using highly concentrated forms of EPA, and the range of DHA dosages across studies is small. Based on our analysis, we are unable to conclude that EPA alone is any more or less effective for CVD prevention than EPA+DHA.6

The same authors (or some of them) have since then published the following papers:

  • Omega-3 and Risk of atrial fibrillation: Vagally-mediated double-edged sword 2025: “Higher consumption of dietary omega-3 is associated with decreased AF risk. In contrast, pharmaceutical dosing of omega-3 increases AF in a dose-dependent manner, which may be mediated by vagal tone.” (as you can see @Shady, dietary omega-3 is not the same as supplementing!)
  • Omega-3 fatty acids in primary and secondary prevention of cardiovascular diseases 2024: “One important question is whether EPA, DHA, or some combination of both is more effective in preventing CVD outcomes. There is the belief that EPA is better for CVD prevention given observations that DHA supplementation can increase LDL-cholesterol levels. One study found high-dose DHA increases LDL turnover and contributes to larger LDL particles compared with EPA; however, large LDL particles are linked to lower risk of CVD as compared to small LDL particles. Regardless, there is a more significant amount of data involving the benefits of Ω-3 PUFAs and atherosclerotic plaque stability with EPA versus EPA + DHA. […] It appears the primary unanswered questions relate to the optimal mix of EPA and DHA and ideal target doses of these Ω-3 fatty acids.”
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#113

The truly concerned person just eats a lot of fish I would think. For fish oil, supplements are for the population. Like vitamin D rather than being in the sun.

There is no food for Zetia or SGLT2s.

Salmon cakes are a staple in our house because of my 16 year old. Thanks for the reminder about sushi - a lot easier and les oil even if a lot more expensive. He would eat it every day I think.

I’m a 5x a week salmon or sardines person.

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#114

Here’s another recent paper: Effects of purified eicosapentaenoic acid versus mixed eicosapentaenoic/docosahexaenoic acid pharmacotherapies on coronary plaque volume: network meta-analysis of prospective coronary imaging trials 2025

Acta Cardiologica. Cedars-Sinai, University of Iowa, UCLA, Mount Sinai, etc.

EPA but not EPA/DHA is associated with reductions in coronary plaque burden when given as adjunct to statins in patients with coronary artery disease.
Across published trials, eicosapentaenoic acid (EPA) is associated with reduced total and lipid coronary plaque volume when administered as adjunct to statins in patients with coronary atherosclerosis.
Mixed eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA) is not associated with reductions in coronary plaque volume.
Adjunctive EPA but not EPA/DHA is superior to statin monotherapy in terms of relative reduction in total and lipid coronary plaque volume.

So we have once again a paper showing benefits for EPA only and nothing for EPA+DHA.

So surely DHA is detrimental. How else could you explain the effect? If A > 0 and A + B = 0 then B < 0. It’s as simple as that. DHA blunts the benefit of EPA.

See also: Higher docosahexaenoic acid levels lower the protective impact of eicosapentaenoic acid on long-term major cardiovascular events 2023 (Stanford, UCSD, University of Utah).

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#115

DHA has always been primarily about boosting cognitive function. The reason the combo didn’t work as well as the monotherapy in the study you mentioned is simply because DHA raises LDL-C levels, which can offset some of EPA’s anti-atherosclerotic benefits. That’s exactly why prescription lipid-lowering drugs use pure EPA. This is no secret at all—it’s been common knowledge for decades, and there’s absolutely no need to prove it all over again.

Even with DHA carrying such a massive debuff, there’s a good reason people still take it together with EPA. The tens of thousands of papers proving DHA’s benefits are exactly what keeps it in the game.

#116

If you’ve done a personalized assessment and decided that DHA isn’t right for you, that’s totally fine. I remember Bryan Johnson also sticks to just EPA. But that is by no means a one-size-fits-all rule.

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#117

Thanks AI.

#118

Instead of giving generic low-IQ answers, can you try to analyze the papers I sent and answer them?

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#119

When a conclusion is already predetermined, even the most flawless paper will be riddled with all kinds of issues. Let the audience be the judge.And for what it’s worth, sardines have a DHA-to-EPA ratio of about 1.5:1. If you believe DHA is harmful, that’s perfectly fine

#120

Dietary omega-3 <> Supplemental omega-3, one example:

Omega-3 and Risk of atrial fibrillation: Vagally-mediated double-edged sword 2025: “Higher consumption of dietary omega-3 is associated with decreased AF risk. In contrast, pharmaceutical dosing of omega-3 increases AF in a dose-dependent manner, which may be mediated by vagal tone.”

I gave my reasoning above as to why I think it could be harmful. You did not contradict it.

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