Associations of epigenetic aging with cortical thickness, brain age gaps, and neuroanatomical heterogeneity

The biological aging process exhibits heterogeneous effects on different tissues, manifesting as tissue-specific variations in structural integrity and functional decline. Previously developed models are able to predict age from DNA methylation in the blood and the difference between estimated epigenetic age and chronological age is suggested to reflect accelerated or decelerated biological aging. While most prior studies have focused on the association between epigenetic age acceleration and global cortical thickness, it remains to be determined whether biological aging varies across specific cortical regions. This study aimed to assess associations between epigenetic age acceleration and regional cortical thickness, brain age gaps, as well as intra- and interindividual neuroanatomical heterogeneity in 756 participants of the BiDirect Study, including 430 participants from the general population and a cohort of 326 individuals with depression. Epigenetic age was estimated from whole blood DNA methylation data using the GrimAge algorithm. We observed an association of epigenetic age acceleration with cortical thinning across almost all cortical regions, suggesting a global association without regional confinement. This result was additionally underpinned by showing that accelerated epigenetic aging was also associated with increased interindividual neuroanatomical heterogeneity in contrast to a lack of association between epigenetic aging acceleration and intraindividual neuroanatomical heterogeneity. Accelerated epigenetic aging was furthermore paralleled by higher neuroimaging-based brain age gaps, suggesting at least partly shared aging processes. Together, these findings highlight that accelerated epigenetic aging reflects a global rather than region-specific neuroanatomical aging process, linking molecular and structural markers of brain aging and underscoring the potential of epigenetic clocks as biomarkers for brain health and neurodegenerative risk.