Second Generation DNA Methylation Age Predicts Cognitive Change in Midlife: The Moderating Role of Childhood...

DNA methylation age (DNAmAge) surpasses chronological age in its ability to predict age-related morbidities and mortality. This study analyzed data from 287 middle-aged twins in the Louisville Twin Study (mean age 51.9 years ± 7.03) to investigate the effect of DNAmAge acceleration on change in IQ (ΔIQ) between childhood and midlife, while testing childhood socioeconomic status (SES) as a moderator of the relationship. DNAmAge was estimated with five commonly used algorithms (Horvath, Horvath Skin and Blood, GrimAge, and PhenoAge). A factor analysis of these measures produced a two-factor structure which we identified as first generation and second generation measures. Results of genetically informed, quasi-causal regression models indicated that accelerated second generation DNAmAge predicted more negative ΔIQ from childhood to midlife, after accounting for genetic and environmental confounds shared by twins. The relationship between DNAmAge and ΔIQ was moderated by childhood SES, with a stronger effect observed among twins from low SES backgrounds. Second generation DNAmAge measures trained to estimate phenotypic biological age show promise in their predictive value for cognitive decline in midlife. Our genetically informed twin design suggested that DNAmAge may represent a biological pathway through which early-life socioeconomic disadvantage impacts midlife cognitive health.