Subtyping and staging of Alzheimer's disease from routine structural MRI with PHASE-AD

Structural MRI is routinely acquired in the clinical assessment of Alzheimer's disease, yet quantitative morphometric indices derived from these scans remain largely confined to research settings. Here we present PHASE-AD - a framework that translates such indices into clinically interpretable classifications of atrophy subtype and stage that jointly capture atrophy progression while accounting for inter-individual atrophy heterogeneity. PHASE-AD is trained on MRI scans from 8,415 participants and robustly captures limbic-predominant and hippocampal-sparing atrophy subtypes that were identified across seven independent datasets. Two cross-validation schemes revealed high robustness across different field strength and scanner manufacturer configurations. Atrophy classifications were associated with diverging clinical profiles and tau accumulation patterns. In prospective designs mirroring contemporary AD trials, they stratified longitudinal cognitive trajectories and outperformed semi-quantitative visual MRI assessments as a clinically established comparator. These findings support the integration of automated atrophy subtyping and staging into clinical practice and pharmacological trials.