#559

Not sure if your post is in response to mine. Just so there is no misunderstanding you should definitely get the shingrix vaccine if you had chicken pox as a child. I was just stating that it doesn’t make sense if you had the varivax vaccine as a child and never got chickenpox. If you never got chickenpox as a child then you should get the varivax vaccine now.

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#560

I am 43 in the UK and had chickenpox as a child. I’m also ApoE4/4. The SHINGRIX vaccine is expensive for me at nearly £500. The NHS only gives this vaccine free when we turn 65 or at 50 if with severe immunosuppression. My take is this is probably money well spent in my position.

Upon further research, it seems most if not all pharmacies won’t vaccinate me until I’m 50.

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#561

Taurine associated with a 26% lower risk of dementia.

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#562

Based on: Association of amine biomarkers with incident dementia and Alzheimer’s disease in the Framingham Study 2018

Ninety-three participants developed incident dementia (mean follow-up=15.6±5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (HR=1.40; 95%CI=[1.15–1.70]; p=8.08×10–4). Glutamic acid (HR=1.38; 95%CI=[1.11–1.72]), taurine (HR=0.74; 95%CI=[0.60–0.92]) and hypoxanthine (HR=0.74; 95%CI=[0.60–0.92]) levels also showed suggestive associations with dementia risk.
We identified four biologically plausible, candidate plasma biomarkers for dementia. Association of anthranilic acid implicates the kynurenine pathway, which modulates glutamate excitotoxicity. The associations with hypoxanthine and taurine strengthen evidence that uric acid and taurine may be neuroprotective.

(not sure you want high uric acid though btw)

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#563

So … I’ll gently disagree. This is a great example of statistical significance, not being the same as clinical significance. So the delta here is 1.6 per 1000 person years. So 1 person in 625/year more likely to have depression? So that person can stop. Not clinically meaningful (unless you are the 1:625).

It is impossible from this data to understand the actual % of the population studied who had depression, but in the US ongoing rate is reported at 8.8% currently, but some estimates are much higher. Yet this dataset has a 1.23-1.39% in a given year. So representative? I don’t know.

Overall, saying DHA causes depression has a result of 1 excess case/year per 625 individuals. Those individuals simply cease. But the 624 who it makes no difference continue.

I cannot see any clinical relevance of this, except to make sure to be aware that if I have a patient on DHA (which will be virtually 100% of my patients) and they have new onset depression - consider the possibility that cessation of DHA might be sensible.

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#564

You might be right, as there was no significant difference in PHQ-8:

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Still:

  1. That’s the best trial we have for omega 3 and mental health and it shows that EPA + DHA increases the risk of depression, this might not be significant but in any case we cannot say that omega 3 help with mood disorders.
  2. Meta-reviews show that only EPA-dominant formulations improve depression. So if EPA alone is antidepressant but EPA + DHA is not, then surely DHA has some negative impact?
  3. When I posted that DHA made me depressed, several other people chimed in: Omega 3 makes me depressed: why?

I think the problem is even worse in APOE4 people: Parkinson's disease - #639 by adssx

  1. Supplemental DHA does not go into their brain
  2. High serum DHA is associated with a HIGHER risk of dementia

So I would not give DHA to:

  • People with a personal or family history of depression or mood disorders and/or
  • APOE4 carriers
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#565

E3/E4 here, and I haven’t noticed anything from fish oil supplementation. Lucky, I guess.

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#566

I think this is complicated. It is interesting that Dr. Dayspring is not on top of this controversy.

He want’s omega 3 index of 10% in those with ApoE4’s. Does it matter if not getting into the brain? Might it be harmful?

Do phospholipids bypass this pathway of the DHA transporter?

There is clearly an age related issue also in the literature, younger people even with apoE4/E4 transport DHA well into their brain, whereas older individuals don’t.

We don’t know, if you start at age 50 years with solid supplementation, if it continues to get absorbed well.

Also ApoE3/E4 or E2/E4 how bad is their absorption to the brain? An E4/E4 is more concerning, but that is only 4-6% of cases of ApoE4 carrying individuals.

For the majority, I’m favoring early use, but ones that have phospholipids or through fish consumption.

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.

4 Likes
#567

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.

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#568

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.

So supplementing with DHA is useless for cognition.

1 Like
#569

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

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#570

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.

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#571

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

#572

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 ?

#573

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 :).

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#574

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.

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#575

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.

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#576

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

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#577

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

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

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

#578

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.

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