APOE ε4 and Dietary Patterns in Relation to Cognitive Function: An Umbrella Review of Systematic Reviews

Context: Carrying the apolipoprotein epsilon 4 allele ( APOE epsilon 4) is the strongest genetic risk factor for late-onset Alzheimer's disease. There is some evidence suggesting that APOE epsilon 4 may modulate the influence of diet on cognitive function. Objective: This umbrella review of systematic reviews evaluates the existing literature on the effect of dietary interventions on cognitive and brain-imaging outcomes by APOE status. Data Sources: PubMed, EMBASE, Web of Science, and Scopus were searched using terms appropriate to each area of research, from their respective starting dates of coverage until March 2023. Data Extraction: Two independent reviewers conducted data extraction and performed a quality appraisal using the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 Data Analysis: Six total reviews were included in the final analysis. Four reviews evaluated randomized controlled trials on individuals aged 50-93 years ranging the entire cognitive continuum. One review combined observational studies and clinical trials conducted on both cognitively healthy and cognitively impaired individuals (age range: 50-90), and 1 review included observational studies of both cognitively healthy and cognitively impaired adults (age range: 50-75). Results: Both observational studies and clinical trials yielded inconclusive results attributed to both practical limitations associated with longitudinal follow-up and issues of methodological quality. Except for the Mediterranean diet, dietary interventions, such as the ketogenic diet, nutraceuticals, and supplements, were generally not effective in older APOE epsilon 4 carriers. This review considers plausible biological mechanisms that might explain why older and cognitively impaired APOE epsilon 4 carriers were less likely to benefit. Conclusion: This review identifies notable gaps in the literature, such as a shortage of studies conducted in middle-aged and cognitively healthy APOE epsilon 4 carriers assessing the impact of dietary interventions and provides suggestions for novel trial designs.