Functional system-specific brain aging across the Alzheimer’s disease continuum

Accelerated brain aging is implicated in Alzheimer’s disease (AD). However, the spatial heterogeneity of brain aging patterns across different functional systems along the AD continuum remains largely unexplored. We developed functional system-specific brain age models derived from structural magnetic resonance imaging in a healthy adult cohort ( n = 22,672) and applied them to 1478 participants across the AD continuum. Using up to 6 years of retrospective longitudinal data before clinical AD conversion, we quantified predicted age differences (PADs) and their change rates, characterized heterogeneous brain aging trajectories, and examined their associations with AD biomarkers, cognitive performance, and clinical progression. Progressive mild cognitive impairment (MCI) individuals showed early PAD deviations in the default mode network and accelerated changes in attention and control networks. System-wise PAD dynamics mediated the effects of AD-related biomarkers on cognitive decline. Integrating PAD features can improve predictive accuracy of MCI-to-AD conversion (AUC = 0.95). Functional system-specific PADs can be sensitive biomarkers for early detection and monitoring of individualized AD risk.