DoubleBond wrote:However, I been unsuccessful in trying to find an independent evaluation of their nutritional content. The box says 660 mg of omega-3 (but does not say if it is per egg? per serving? per box?). Also, what kind of omega-3? How much ALA vs DHA and EPA? If the omega-3 is mostly ALA, maybe it is not such a good source, as only a small percentage will be converted to DHA and EPA. Does anybody know?
Background: Past clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment.
Methods: 33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition.
Findings: A 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups.
Interpretation: Dementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers.
DoubleBond wrote:New paper by a group from the Keck School of Medicine shows that daily supplementation of 2g DHA in triglyceride form increases DHA in the brains of APOE4's - just not as much as for APOE3's:
Direct comparisons of the different formulations do not support an advantage for TG or PL-based formulations on plasma levels , although animal models indicate that PL-DHA may increase in the brain more efficiently than other formulations . Unesterified fatty acids and specific phospholipids such as lysophosphatidylcholine (LPC DHA) are the preferred brain DHA substrates . Following absorption, dietary TG-DHA is hydrolyzed by lipases to produce free or unesterified DHA and LPC DHA. A second phase PL-DHA is produced from hepatic metabolism of TG-DHA. When in free fatty acid form, DHA detaches from albumin in the plasma and is transported via passive diffusion across the outer membrane of the blood-brain barrier (BBB) . LPC DHA is transported along the inner membrane of the BBB via the major facilitator superfamily domain-containing 2a (MFSD2a) receptor . Accordingly, LPC DHA formulations may produce faster enrichment of brain DHA concentrations than TG-based DHA formulations  [This footnote cites Rhonda], but this has not yet been demonstrated in human studies.
In the current study, we observed an increase in EPA levels after DHA supplementation which is likely secondary to retroconversion from DHA. Although acute carbon tracer studies suggest minimal retroconversion of DHA to EPA in tissues , longer-term DHA supplementation leads to an increase in circulatory EPA by up to 10% [54,55]. This process involves peroxisomal oxidation of DHA and occurs in both astrocytes and hepatocytes . Furthermore, the EPA content of the n-3 FA capsules provided in this trial was very small (<0.1%), making it a less plausible explanation for the observed increase in plasma or CSF EPA levels following supplementation. The lower rate of retroconversion of DHA to EPA in APOE4 carriers may signify peroxisomal dysfunction. Peroxisomes play a key role in the production of reactive oxygen species and contribute to the oxidation of long-chain PUFAs . In AD mouse models, decreased efficiency of peroxisomal b-oxidation was observed in the hippocampus and was associated with the accumulation of toxic very long chain fatty acids . It is plausible that older APOE4 carriers with evidence of oxidation markers in tissues may not benefit from n-3 FA supplementation, underscoring the need for early intervention.
EPA plays fundamental roles in neuroinflammation and neural proliferation processes [,]. EPA can work to attenuate the effects of inflammatory mediators such as interleukin-1b (IL-1b) via various cell signaling pathways . EPA also serves as a source of eicosanoids and resolvins involved in mitigating inflammation and excitotoxicity in the brain [,]. This finding contributes to our understanding as to why APOE4 carriers with limited omega-3 intake might be at a greater risk of neuroinflammation and AD progression .
APOE4 non-carriers showed a trend toward greater CSF DHA levels and significantly greater EPA levels compared with APOE4 carriers. Lower CSF DHA and EPA levels in APOE4 following DHA supplementation could result from lower brain uptake or greater brain consumption.
The Brain DHA Delivery Trial will examine the effect of APOE genotype on the changes of cerebrospinal fluid (CSF) DHA to Arachidonic acid (AA) ratio in 160 cognitively healthy older individuals in response to DHA supplementation. Randomized clinical trials have yielded mixed results on the effect DHA supplementation on cognitive outcomes. This study asks the critical question of whether DHA gets into the brain in sufficient amounts after supplementation, and whether APOE genotype affects brain penetrance.
This trial will also test the effect of DHA supplementation on changes in brain structural and functional connectivity assessed by MRI, and changes in cognition after two years of supplementation in all 320 participants.
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