The value of brain age as a transdiagnostic biomarker of neurodegeneration

Progressive structural brain changes are a hallmark of neurodegenerative conditions like Alzheimer's disease (AD), frontotemporal dementia (FTD), multiple sclerosis (MS), and Parkinson's disease (PD). The brain-predicted age difference (brain-PAD) has emerged as a promising biomarker to quantify these alterations, yet its unique clinical contribution relative to conventional measures of global brain atrophy such as the brain parenchymal fraction (BPF) remains underexplored. In this transdiagnostic study across AD, FTD, MS, and PD, we systematically evaluated brain-PAD's capacity to distinguish patients from controls, its cross-sectional and longitudinal associations with cognition, and its voxel-wise structural correlates. We benchmarked brain-PAD against BPF to determine its added explanatory value. Brain-PAD successfully distinguished patients from controls, adding to BPF alone, in AD, FTD, and MS, but not PD. Across disorders, higher brain-PAD correlated with worse cognition, showing clear added value beyond BPF particularly in AD and MS. Baseline brain-PAD also independently predicted subsequent cognitive changes in AD, FTD, and MS, over and above BPF. Voxel-wise analyses revealed spatial features underlying brain-PAD including, beyond global tissue loss, specific regional atrophy matching each disease's characteristic pattern. Collectively, these findings demonstrate that brain-PAD is a clinically meaningful, transdiagnostic biomarker of neurodegeneration that complements conventional volumetric measures like the BPF.