Omega-3 polyunsaturated fatty acids in neurodegenerative disorders: Mixed designs = mixed results

Epidemiological studies consistently show an elevated intake of fish and long-chain omega-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduces the risk of developing neurodegenerative diseases, particularly dementia and Alzheimer's disease. These observations are supported by preclinical research, where a range of potential mechanisms have been identified, such as increasing neurogenesis, or regulating inflammation and neuroinflammation via the production of bioactive lipid mediators. However, the results of clinical trials have been inconsistent and mixed, and this may be due to the considerable heterogeneity in trial designs, but also a lack of appreciation of methodological complications unique to omega-3 PUFA research. In this review, we explore omega-3 PUFA specific methodological considerations based around participant selection and trial design. Participant-related aspects include baseline cognitive status, age, sex and genotype, whereas methodological aspects include placebo selection, DHA vs. EPA, chemical form and quality of the omega-3 PUFA preparation, and wider nutrient interactions. We also suggest how consideration of these factors should be included in the design and reporting of clinical trials, with the aim of increasing the validity and reproducibility of research in the field.