Diversity-Sensitive Brain Clocks Linked to Biophysical Mechanisms in Aging and Dementia

Abstract

Brain clocks track the deviations between predicted brain age and chronological age (brain age gaps, BAGs). These BAGs can be used to measure accelerated aging, monitoring deviations from the healthy brain trajectories associated with brain diseases and different cumulative burdens. However, the underlying biophysical mechanisms associated with BAGs in aging and dementia remain unclear. Here we combine source space connectivity (via electroencephalography) with generative brain modeling in healthy controls from the global south and north, alongside patients with Alzheimer's disease and behavioral variant frontotemporal dementia (bvFTD) (N = 1,399). BAGs in aging were influenced by geography (south > north), income (low > high), sex (female > male) and education (low > high), with larger BAGs in patients, especially females, with Alzheimer's disease. Biophysical modeling revealed BAGs related to hyperexcitability and structural disintegration in aging, while hypoexcitability and severe disintegration were linked to dementia. Our work sheds light on the biophysical mechanisms of accelerated aging and dementia in diverse populations.