Among 104 cognitively normal older adults enriched for preclinical Alzheimer's disease (69.2% preclinical AD, 44.2% APOE4 carriers), higher serum DHA+EPA levels correlated with greater gray matter volume in the left precuneus/postcentral gyrus and lower amyloid-beta (Aβ) burden in the frontoparietal cortex bilaterally. The amyloid association was especially pronounced among APOE4 carriers, who showed reduced global and AD-regional Aβ at higher omega-3 levels — a genetically high-risk group for whom few modifiable interventions have shown clear benefit.
This cross-sectional finding is notable for two reasons: it uses objective PET-derived amyloid imaging rather than surrogate endpoints, and it targets a preclinical window before irreversible neurodegeneration sets in. The APOE4-specific signal is intriguing and aligns with mechanistic hypotheses that DHA modulates lipid metabolism pathways through which APOE4 impairs amyloid clearance. However, causality cannot be established here — higher omega-3 status may simply reflect a healthier diet broadly, and reverse causation is possible if early neurodegeneration alters fatty acid metabolism. The sample size of 104 is modest, the cohort skews female (67%), and baseline cross-sectional designs cannot confirm that supplementation would produce similar effects. As the authors acknowledge, randomized trials combining EPA and DHA with amyloid PET endpoints are conspicuously absent from the literature. This study strengthens the rationale for such trials, particularly in APOE4 carriers, but is not yet actionable evidence for supplementation.