Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer's Disease Cooperative Study-Sponsored DHA Clinical Trial

Background: Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) play key roles in several metabolic processes relevant to Alzheimer's disease (AD) pathogenesis and neuroinflammation. Carrying the APOE ϵ4 allele (APOE4) accelerates omega-3 polyunsaturated fatty acid (PUFA) oxidation. In a pre-planned subgroup analysis of the Alzheimer's Disease Cooperative Study-sponsored DHA clinical trial, APOE4 carriers with mild probable AD had no improvements in cognitive outcomes compared to placebo, while APOE 4 non-carriers showed a benefit from DHA supplementation. Objective: We sought to clarify the effect of APOE ϵ4/ϵ4 on both the ratio of plasma DHA and EPA to AA, and on hippocampal volumes after DHA supplementation. Methods: Plasma fatty acids and APOE genotype were obtained in 275 participants randomized to 18 months of DHA supplementation or placebo. A subset of these participants completed brain MRI imaging (n = 86) and lumbar punctures (n = 53). Results: After the intervention, DHA-treated APOE ϵ3/ϵ3 and APOE ϵ2/ϵ3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to ϵ4/ϵ4 carriers. APOE ϵ2/ϵ3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to ϵ4/ϵ4 carriers. The change in plasma and cerebrospinal fluid DHA/AA was strongly correlated. Greater baseline and increase in plasma EPA/AA was associated with a lower decrease in the right hippocampal volume, but only in APOE 4 non-carriers. Conclusion: The lower increase in plasma DHA/AA and EPA/AA in APOE ϵ4/ϵ4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation.