Premature epigenetic aging, deviations from normative brain development, and cognitive performance in young adulthood

Premature epigenetic aging has been linked to poorer cognitive performance, but the neuroanatomical pathways underlying this association remain unclear. Therefore, we tested whether premature epigenetic aging predicts deviations from normative brain development and cognition in young adulthood. We followed 254 young adults from the ELSPAC prenatal birth cohort. Epigenetic aging was estimated using Horvath's DNA methylation clock, CheekAge, and AltumAge. Structural MRI was processed with FreeSurfer to derive cortical thickness and surface area in 68 Desikan-Killiany regions and subcortical volumes in 14 Aseg regions. CentileBrain normative models trained on 37,407 MRI scans from individuals aged 3-90 years were used to quantify age- and sex-specific deviations from normative brain development. Cognitive performance was assessed using the WAIS-IV. Premature epigenetic aging estimated using Horvath's clock was associated with more negative deviations from normative volume of the putamen and caudate, but not with other subcortical volumes, cortical thickness, or surface area. In women, this premature epigenetic aging was also associated with lower full-scale IQ and performance IQ, and moderated mediation analyses indicated that the deviations in putamen volume mediated the relationship between premature epigenetic aging and cognitive performance. In men, the relationship between premature epigenetic aging and cognitive performance was quadratic (U-shaped). No similar effects were observed when using CheekAge or AltumAge.Premature epigenetic aging estimated using Horvath's clock and the associated deviations in development of the dorsal striatum in young adulthood may represent an early marker of poorer cognitive performance long before clinical symptoms might emerge.