DHA supplementation decreases the brain uptake of DHA and AA?

#1

Dynamic PET-MR imaging with 18F-labeled polyunsaturated fatty acid tracers for monitoring the effects of docosahexaenoic acid supplementation in ApoE4-targeted replacement mice 2025

Results: Preliminary static analysis suggests that DHA supplementation decreases the brain uptake of DHA and AA, as measured by SUVs. Kinetic analysis of dynamic PET data, which provides a more accurate assessment of DHA and AA uptake into the brain, enabled the calculation of Irr2TCM K* values. This analysis utilized an image-derived input function and accounted for variations across animals in VB.

You read it here first: DHA is detrimental to your health and make sure you don’t take omega 3 as DHA!

Details on why DHA supplementation is bad: Vitamin O (Omega 3) for athletes - #4 by adssx

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#2

It’s DHover.
Sadly most omega 3 supplements come with at least some DHA…

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#3

Certainly continuous DHA supplementation seems like a clear negative, for many reasons. I personally have never supplemented with DHA (and EPA only in the past couple of years). However.

Fish contains on average more DHA than EPA. Has regular fish consumption been shown to be brain negative? We do know, that supplementing with DHA in addition or concomitantly with fish does not rescue the negative effects of DHA, which would imply that there is nothing special in the fish food matrix that modifies DHA bio kinetics. Or?

Furthermore, as DHA is distributed in more tissues than just the brain, what would be the impact of intermittent DHA bolus (say, once a week)? We know there’s a clear difference in intermittent vs continuous (after all, we do it with rapa), basically a pulsed intake.

An intervention that has a seemingly negative impact acutely, need not have such longer term, or intermittently or dosage dependent - thousands of well known examples - exercise, impact of certain FA on endothelial function, coffee and BP and BG impact and on and on and on. Hormesis too. We all know this.

So a single image tells me something, but not everything. The scientific method means that we need to prove outcomes, not just rely on extrapolation, however tempting that may be.

We already have some outcome studies of DHA supplementation. On the whole, not very encouraging. But. We do not have - that I am aware of - outcome studies exploring other modalities of supplementation, such as once weekly pulsed. And again, what about fish consumption? Is the rest of the stuff in fish so beneficial that it offsets the negative of DHA? I think that needs to be shown, and there is reason to doubt it, as fatty fish has more DHA, yet is supposedly healthier - it needs to be shown. We can speculate mechanistically all we want, but the proof is in the pudding.

Metabolism and functions of docosahexaenoic acid‐containing membrane glycerophospholipids

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#4

Of note: the author of this paper (Hussein Yassine) was behind the failed PreventE4 trial (DHA 2 g/day: PreventE4: evaluating the role of omega-3 in cognitive health and Alzheimer’s disease | VJDementia ). So it seems that he switched his research from “Let’s show that DHA is neuroprotective” to “Let’s show why DHA is not neuroprotective”.

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#5

This is why we have clinical trials, so people can’t ad nauseam push supplements like DHA on to the masses with their obfuscated health claims.

It’s really simple. The DHA henchmen of the supplement industry just needs to fund clinical trials for their unproven health claims. If it’s dementia, that’s a DHA double blind study on dementia rates. If it’s CVD, it’s a trial on MACE. Mars did a study on CVD and cacao, it’s doable (Though I haven’t read it).

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#6

The dose is used here was hundreds of times more than even generous dosing in humans. I’m not sure how much this study can inform the value or danger of human DHA supplementation.

#7

Check the other thread with the genetic studies and clinical trials.

#8

You’re right that the dose used is crazy high (7 g/kg in mice, equivalent to ~40 g/day for a human?). We need the full paper to understand why they chose that dose.

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#9

Hi adssx, I’m around at 80 kg so x 7 g per kilogram would be 560 g per day without allometric scaling, but even with, the dose would be crazy high. Most people supplement with just a few grams per day.

It’s always a good idea to read the full article before drawing conclusions, but I’m not sure I’m going to take the time for this one. :slight_smile:

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#10

I could be wrong, but I think you’re reading too much into this. They’re talking about a reduced rate of uptake of an incremental labeled dose of DHA after long-term high-dose supplementation. Note the Figure caption: “Images are from the 10-30 min window post injection of the tracer”. It wouldn’t be surprising if the brain (either the tissue or the BBB) more avidly took up or incorporated incremental DHA when levels are low or physiological, and it took up or incorporated DHA more slowly when highly replete. It would kinda be problematic if it wasn’t.

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#11

So … taking fish in the diet, before Alzheimer’s Changes occur seems to rate reduce those with ApoE4’s (and presumably even better in those without ApoE4’s) getting AD. There is also a solid relationship in those without ApoE4’s. The issue is, once there is MCI or AD, I don’t think we have any evidence of benefit.

From my perspective, the issue with supplements, unless they have phospholipids, or perhaps if money is no object plasminogens, is an issue of brain penetrance, especially in those with ApoE4s.

Pushing levels too high isn’t a great choice and in general I don’t recommend over 1000 mg/day total. The strategy of pushing EPA has some validity, but overall, my assessment - at least how I’m clinically implementing is to favor having fish, and supplement with Omega 3’s with a decent mix of DHA/EPA with phospholipids or plasminogens.

  • A dose-response meta-analysis of observational studies I in Nutrition Reviews found that up to 2 portions of fish per week reduced Alzheimer’s disease (AD) risk by 30% (RR: 0.54–0.89; N = 3 studies) and all-cause dementia by 10% (RR: 0.79–1.02; N = 5 studies) 1.
  • A cross-sectional analysis in JAMA II of 286 autopsied brains showed that seafood consumption (≥1 meal/week) was significantly correlated with less AD pathology in APOE4 carriers, including lower neuritic plaques (β = –0.69; 95% CI: –1.34 to –0.04) and neurofibrillary tangles (β = –0.77; 95% CI: –1.52 to –0.02) 2.
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#12

@CronosTempi, any thoughts on daily consumption of High DHA fish oil (with DHA 500mg + EPA 100mg) x 2 = Daily total of 1,000mg DHA + 200mg EPA ,… In reference to the cited article, is this a net negative ?

#13

Daily DHA seems a net negative (but based on more than a single paper). Pulsatile, like for example once weekly, not enough data. The issue is that while DHA is vital, there are problems with supplementing - it somehow interferes with endogenous conversion, so you end up with less available - very paradoxical (I posted a paper to that effect). So it’s supplementing that’s problematic. There are claims that certain forms of DHA are OK to supplement, but I don’t see that as proven. I personally stick to modest EPA and a lot of dietary ALA. I also consume fish twice weekly. There may be an issue with age, conversion becoming less efficient, but that’s getting into the weeds.

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#14

Neuroticism, omega-3 fatty acids, and risk of incident dementia 2025

Omega-3 fatty acids, especially docosahexaenoic acid (DHA), were inversely associated with both neuroticism and dementia risk.
Causal relationships were confirmed, showing that neuroticism leads to lower DHA levels, which in turn contribute to greater cerebrovascular burden.
Mendelian randomization analysis suggested that high levels of neuroticism reduce DHA levels, which, in turn, contribute to white matter pathology, a hallmark of VaD.

So cognitive issues cause low DHA rather than the other way around?

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#15

OK, let’s assume so. However, I would highlight another sentence from your quote:

“Mendelian randomization analysis suggested that high levels of neuroticism reduce DHA levels, which, in turn, contribute to white matter pathology, a hallmark of VaD.”

Neuroticism —-> Low DHA —-> VaD.

In this scenario, the problem with “neuroticism” is that it leads to “low DHA”, and if “low DHA” leads to, i.e. is causative (rather than just associated with) per the passage you quoted and I highlighted, of Vascular Dementia, then if we can prevent the lowering of DHA, then assuming this is the causative mechanism, we should be able to prevent the white matter pathology that’s a hallmark of VaD.

Neuroticism can be characterized as “cognitive issues” as you have done in your statement I quoted first. But note, neuroticism in and of itself is not diminishment of intellectual ability like in dementia, but more along the lines of a personality disorder. If you can abolish the downstream effect of prolonged neuroticism (in this scenario) resulting in the lowering of DHA, then prolonged neuroticism should not result in white matter pathology development in vascular dementia and will just remain a personality disorder.

That would argue for finding a means of preventing the decline of DHA (which according to the mechanism that paper outlined) leads to VaD downstream from neuroticism.

But whether supplementing with DHA in fishoil form is the optimal way of raising DHA levels in the brain (or other tissues) is a whole different question - and I have previously posted the paper showing the paradoxical impact of exogenous DHA on the endogenous status of DHA. Yes, DHA in the brain (and other tissues) is important, but that doesn’t mean you can just supplement with DHA in pills and have that translate to proper incorporation into brain tissue.

So even if “low DHA” —-> “VaD”, doesn’t mean “supplemental DHA pills” —-> “adequate DHA levels”. IOW, a neurotic person supplementing with DHA pills might not prevent the development of VaD.

Bottom line, the story of DHA function and levels in the brain (and other tissues), must be considered within the context of “and how exactly do we control those levels”, because it’s not simply by supplementing with DHA pills. We can also ask “does serum DHA translate into DHA incorporation in brain (and other) tissue”? Because maybe supplemental DHA raises serum levels while suppressing incorporation into tissue. Endogenous DHA conversion incorporates DHA into tissues (including brain) - we know this, because even people who don’t consume any long chain marine (or animal) omega-3 FA, don’t lack DHA in their tissues - if they did lack, then all vegans would be dead because omega-3 FA are essential FA. And we have lifelong vegans in many cultures on a multigenerational scale. They do it by converting short chain ALA n-3 to DHA. Studies show that vegans DHA status is just as high (and according to many studies higher!) than omnivores. And again as in the paper I posted previously, supplemental exogenous DHA interferes with that conversion, thus being a net negative. It is therefore crucial to make a distinction between the importance of “tissue DHA” status and “supplemental exogenous DHA”.

#16

Not exactly:

We used WMH as a proxy for VaD due to the lack of genome-wide association studies (GWAS) data and valid genetic instruments for VaD (Ikram et al., 2017).
MR analyses showed that neuroticism causally linked to lower omega-3 fatty acid levels (DHA, DHA% and omega-3 % of total fatty acids) and the degree of unsaturation. Neuroticism also causally increased the omega-6/omega-3 ratio. Further, DHA causally linked to lower WMH volume (Fig. 3; details in eTable 9). Other metabolites showed consistent directional associations with WMH volume and neuroticism, although these associations were not statistically significant. No causal links were found between any metabolites and AD.
GWAS of VaD are generally underpowered and use heterogeneous diagnostic criteria, resulting in a lack of reliable genetic instruments for MR analysis (Ikram et al., 2017).

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So:
Neuroticism → Lower DHA → Higher WMH volume

But low DHA does not cause AD and we don’t know if low DHA causes VaD or not.

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#17

Actually, doesn’t the chart imply that high DHA is linked to lower WMH volume? [Yes: edited]

#18

You mean the forest plot? I see lower DHA (shifted to the left) and corresponding lower WMH (shifted to the left). And higher AD (shifted to the right).

But AD is Alzheimer’s disease, a specific form of dementia. VaD is vascular dementia without the hallmarks of Alzheimer’s.

By the way, interesting epidemiological factoid: Japan has much higher levels of seafood consumption (compared to the Western diets). Fish are high in DHA. Japan has low levels of AD, but high levels of VaD. High DHA, but high VaD? Of course these are just population level epidemiological studies, but still somewhat interesting. After all, Japan also has higher smoking rates and smoking is associated with dementia.

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#19

No, it’s high DHA => lower WMH volume, which is good as white-matter hyperintensities are considered bad (that confused me). I’ll edit my message above.

No: two MR methods are a bit shifted to the right, while one is shifted to the left. None are statistically significant, though.

(And I know what VaD is :wink: )

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#20

@adssx @CronosTempi

So, for the people in the cheap seats, are we still off DHA? :slight_smile:

I’m taking it 1-2x per week as a vegan to emulate me being a fish eating person (thank you cronos). EPA on most other days.