DHA in Alzheimer's Disease: The translational gap between mechanistic complexity and clinical inconsistency

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive dysfunction. Docosahexaenoic acid (DHA), the most abundant ω-3 polyunsaturated fatty acid (PUFA) in the brain, is essential for neuronal structure and function. Although epidemiological studies generally associate higher DHA intake or blood levels with better cognitive outcomes, clinical findings remain inconsistent, partly because DHA intake is closely linked to healthier dietary patterns and lifestyles. This review summarizes the role of DHA in AD from mechanistic, epidemiological, and clinical perspectives. We first discussed its effects on Aβ and tau pathology, synaptic function, neuroinflammation, oxidative stress, mitochondrial function, and brain lipid homeostasis. We then evaluate epidemiological and clinical evidence, with particular attention to factors contributing to heterogeneous responses, including disease stage, ApoE ε4 genotype, sex difference, intervention exposure, and participant characteristics. We propose that individuals with early and potentially modifiable pathology, together with sufficient cerebral DHA availability, may be more likely to benefit from DHA intervention. Finally, we discussed translational strategies, including combination interventions, brain-targeted delivery, and optimized clinical trial design. Overall, this review develops a conceptual framework linking brain lipid homeostasis, molecular mechanisms, clinical heterogeneity, and individualized intervention, providing a basis for understanding differential responses to DHA and improving its clinical translation.