Epigenetic Aging and Cognitive Performance in General and Psychiatric Populations: A Systematic Review and Narrative Synthesis

Epigenetic aging and age-related cognitive decline both show substantial variability across individuals. While a potential link between the two is increasingly being studied in both general and psychiatric populations, a systematic review has not yet been performed. This review summarizes the state of the current literature as well as critical evaluation and suggestions for future research. A literature search (October 31, 2024) identified original peer-reviewed studies examining epigenetic aging and cognitive function in general and/or psychiatric populations following a preregistered protocol (PROSPERO Registration No. CRD42024608024). Other article types or non-English language works were excluded. A total of 57 observational studies (n General = 51, n Psychiatric = 6) were included, with a total number of 37,516 participants in 47 cross-sectional studies and 15,551 participants in 27 longitudinal assessments. Sixteen tools of epigenetic age estimation were investigated, mainly in peripheral blood (n = 53). Quality assessment with the Agency for Healthcare Research and Quality checklist showed low risk of bias in 93% of studies. Great heterogeneity existed in cohort characteristics, cognitive tests, epigenetic age assessments, use of covariates, and statistical modeling. Overall, significant associations of cognitive measures with epigenetic aging measures were found in 43 studies, 5 of which included psychiatric patients. Evidence supported a link between epigenetic age acceleration and worse cognitive performance in 21/38 (55%) studies. In conclusion, the current literature shows encouraging results, but studies with psychiatric populations remain scarce. To establish epigenetic aging tools as biomarkers of premature cognitive aging, more research is needed.