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 epsilon 4 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 APOE4 non-carriers showed a benefit from DHA supplementation. Objective: We sought to clarify the effect of APOE epsilon 4/epsilon 4 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 epsilon 3/epsilon 3 and APOE epsilon 2/epsilon 3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to epsilon 4/epsilon 4 carriers. APOE epsilon 2/epsilon 3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to epsilon 4/epsilon 4 carriers. The change in plasma and cerebrospinal fluid DHA/AAwas strongly correlated. Greater baseline and increase in plasma EPA/AAwas associated with a lower decrease in the right hippocampal volume, but only in APOE4 non-carriers. Conclusion: The lower increase in plasma DHA/AA and EPA/AA in APOE epsilon 4/epsilon 4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation.