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Background and purpose: The present study aimed to explore whether and how omega‐3 (ω‐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 ε4 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 ω‐3 supplementation with APOE ε4 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 ω‐3 at baseline than those stable, for whom the difference remained significant only amongst APOE ε4 carriers (p < 0.01). The interaction term (APOE ε4 × ω‐3) accounted for a significant amount of variance in cognition and cerebral amyloid burden. Long‐term ω‐3 use protected cognition (especially memory function) and lowered amyloid burden and AD risk only amongst APOE ε4 carriers. Mediation analysis suggested that amyloid pathologies, brain reserve capacities, and brain metabolism mediated the relationships of ω‐3 use with memory and global cognition for APOE ε4 (+) carriers. Similar interaction and mediation effects were also indicated amongst high‐risk subjects defined by polygenic hazard scores. Conclusions: Long‐term ω‐3 intake may have a role in AD prevention in genetically at‐risk populations. [ABSTRACT FROM AUTHOR]