Omega-3 Fatty Acids and Alzheimer’s Disease: Toward a New Understanding of Neuroprotective Mechanisms and Intervention Strategies

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Despite recent advances, current therapies offer little benefit, and AD remains a significant challenge. Polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have attracted attention for their neuroprotective effects primarily through anti-inflammatory and antioxidant properties, but also for their ability to influence membrane fluidity and neuronal function. DHA is the predominant omega-3 PUFA in nerve cell membranes and is critical for synaptic plasticity and cognitive function. Some evidence has demonstrated that marine omega-3 supplementation reduces Aβ deposition, modulates microglial activation, and prevents cognitive decline in animal models. Even with heterogeneous results, preclinical and clinical studies suggest that long-term DHA/EPA supplementation can improve cognitive function in subjects with mild cognitive impairment (MCI) and reduce neuroinflammation markers. However, individual variability and brain bioavailability pose significant challenges. This review summarizes and discusses the current knowledge on the importance of PUFAs for human health, exploring novel mechanistic hypotheses, such as the effect of omega-3 fatty acids on brain iron homeostasis, the microbiota–gut–brain axis, the glymphatic system, and miRNAs. Furthermore, it focuses on the therapeutic potential of PUFAs in the treatment of AD and proposes future directions for translational research.