Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers A Review

IMPORTANCE The apolipoprotein E epsilon 4 (APOE4) allele identifies a unique population that is at significant risk for developing Alzheimer disease (AD). Docosahexaenoic acid (DHA) is an essential omega-3 fatty acid that is critical to the formation of neuronal synapses and membrane fluidity. Observational studies have associated omega-3 intake, including DHA, with a reduced risk for incident AD. In contrast, randomized clinical trials of omega-3 fatty acids have yielded mixed and inconsistent results. Interactions among DHA, APOE genotype, and stage of AD pathologic changes may explain the mixed results of DHA supplementation reported in the literature. OBSERVATIONS Although randomized clinical trials of omega-3 in symptomatic AD have had negative findings, several observational and clinical trials of omega-3 in the predementia stage of AD suggest that omega-3 supplementation may slow early memory decline in APOE4 carriers. Several mechanisms by which the APOE4 allele could alter the delivery of DHA to the brain may be amenable to DHA supplementation in predementia stages of AD. Evidence of accelerated DHA catabolism (eg, activation of phospholipases and oxidation pathways) could explain the lack of efficacy of omega-3 supplementation in AD dementia. The association of cognitive benefit with DHA supplementation in predementia but not AD dementia suggests that early omega-3 supplementation may reduce the risk for or delay the onset of AD symptoms in APOE4 carriers. Recent advances in brain imaging may help to identify the optimal timing for future DHA clinical trials. CONCLUSIONS AND RELEVANCE High-dose DHA supplementation in APOE4 carriers before the onset of AD dementia can be a promising approach to decrease the incidence of AD. Given the safety profile, availability, and affordability of DHA supplements, refining an omega-3 intervention in APOE4 carriers is warranted.