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

Abstract Context Carrying the apolipoprotein ε4 allele (APOE ε4) is the strongest genetic risk factor for late-onset Alzheimer’s disease. There is some evidence suggesting that APOE ε4 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 ε4 carriers. This review considers plausible biological mechanisms that might explain why older and cognitively impaired APOE ε4 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 ε4 carriers assessing the impact of dietary interventions and provides suggestions for novel trial designs.