A gene-environment interplay between omega-3 supplementation and APOE ε4 provides insights for Alzheimer's disease precise prevention amongst high-genetic-risk population

Background and purpose: The present study aimed to explore whether and how omega-3 (omega-3) supplementation could interact with genetic factors to modulate cognitive functions, amyloid pathologies, and Alzheimer's disease (AD) risk. Methods: A total of 1,670 non-demented participants (mean age 73 years, 47% females, 41% APOE epsilon 4 carriers) were followed up for 10 years. Hierarchical regressions, linear mixed-effects models, and Cox proportional hazards models were used to examine the interaction effects of omega-3 supplementation with APOE epsilon 4 and polygenic hazard scores, after adjusting for age, gender, education, cognitive diagnosis, insomnia, depression, anxiety, and cardiovascular risk score. Results: Individuals who progress to AD during the follow-up tend to take a shorter duration of omega-3 at baseline than those stable, for whom the difference remained significant only amongst APOE epsilon 4 carriers (p < 0.01). The interaction term (APOE epsilon 4 x omega-3) accounted for a significant amount of variance in cognition and cerebral amyloid burden. Long-term omega-3 use protected cognition (especially memory function) and lowered amyloid burden and AD risk only amongst APOE epsilon 4 carriers. Mediation analysis suggested that amyloid pathologies, brain reserve capacities, and brain metabolism mediated the relationships of omega-3 use with memory and global cognition for APOE epsilon 4 (+) carriers. Similar interaction and mediation effects were also indicated amongst high-risk subjects defined by polygenic hazard scores. Conclusions: Long-term omega-3 intake may have a role in AD prevention in genetically at-risk populations.