Does concurrent supplementation with select B vitamins (B3, B6, B12) change the picture? Or concurrent supplementation with brain penetrant antioxidant cell membrane stabilizers like certain carotenoids (astaxanthin etc.)? When you consume certain fish, carotenoids come bundled in with the various forms of fish oil. Look at choline. Fish come with choline. Supplementing with choline by itself can raise TMAO levels. Fish already have TMAO, and can raise blood levels, at least transiently(*). Yet in general, there doesn’t seem to be evidence of increased atherosclerosis as a result of fish consumption, even though TMAO otherwise can be an exacerbating factor in CVD. Perhaps the supplementation with fishoil alone is suboptimal insofar as its effects are not modified by other molecular constituents found in whole fish. Maybe stick to modest fish consumption?
(*) Circulating trimethylamine N-oxide levels following fish or seafood consumption
I would’ve been interested in another arm without the B-vit supplementation. That way, you could be justified in the “alone” claim, otherwise I don’t see how you can claim “alone”, if a study can show differential effects of (fishoil + vit.B) vs (fishoil). I would also like to see (astaxanthin + Fishoil) vs (astaxanthin) vs (fishoil) - all of these in one trial, not just different trials with separate supplementation.
Fish is a complex biological package, not just a vehicle for EPA and DHA. When you eat fish, you are consuming a synergistic “food matrix” that includes:
High-quality, easily digestible protein
Crucial trace minerals like selenium and iodine
Vitamin D and B vitamins
Astaxanthin, a potent antioxidant (found in pink fish like salmon and trout) that naturally protects lipids from damage.
These compounds work together to lower systemic inflammation. Furthermore, eating fish fundamentally improves your overall diet through the displacement effect. A dinner of sardines or salmon naturally replaces a meal that might otherwise feature red meat or highly processed foods. Taking a supplement alongside a poor diet does not correct the underlying dietary pattern.
But, then again when I eat fish, I eat fish & chips.
High-dose DHA achieved CNS target engagement in non-demented older adults with low baseline omega-3 intake, independent of APOE ε4. Despite biochemical target engagement, no differences in cognition or brain structure were observed over 24 months. Future research should prioritise brain DHA metabolism over further supplementation trials.
DHA supplementation as monotherapy may be insufficient when multiple pathophysiological processes drive neurodegeneration and alter the fate of DHA in the brain
Incorporating more sensitive markers of neurodegeneration, including plasma phosphorylated tau, neurofilament light chain, advanced imaging markers (e.g., DHA PET), or detailed neuropsychological assessments targeting subtle executive function changes could improve the detection of treatment effects.
While 24-month trials are feasible and commonly used, the stability of outcomes in healthy populations over this period may necessitate either longer trials (36 months or longer as suggested by LipiDiDiet extended follow-up). Future work should shift from uniform supplementation toward mechanistic studies of brain DHA metabolism and personalised multimodal strategies that integrate genotype, lipid and inflammatory biomarkers, and more sensitive CNS endpoints to identify the subgroups most likely to benefit.
Fish Oil Doesn’t Protect Aging Brains? Not Even High-Dose DHA Supplements Improved Memory In 2-Year Trial
Here’s what I am wondering - many advocates of DHA supplementation (such as Nick Norwitz) explain away apparent failures of supplementation as down to most forms of DHA not actually reaching the brain. Does this study alter any of that explanatory framing, given that now we see supplemental DHA actually definitely reaching the brain and yet still not being helpful in key dementia metrics. As I recall, there’s even a company promoted by Nick Norwitz that sells (at a very steep markup!) a special form of DHA which supposedly definitely gets into the brain as an anti AD supplement.
I suppose now it could be argued that “enzymes in the brain may actively break down DHA after it arrives, possibly undoing any benefit before it can build up”, but that’s a new explanation trying to rescue the explanation that failed, and it too would need some kind of evidence beyond a simple assertion.
All in all this does not look encouraging for the ApoE4 carriers hoping to prevent, slow down or ameliorate AD/dementia through DHA supplementation. I’d say there’s more hope for rapamycin in this context than DHA, although of course we would need some good extended human trials to show effects either way.