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Parkinson's disease (PD) exhibits high heterogeneity in disease progression, complicating management and increasing required sample sizes for clinical trials. This study evaluates Brain Age Gap (BAG)-the difference between brain age and chronological age-for predicting disease progression in PD. Structural MRI-derived gray matter volumes were analyzed for 451 early-stage PD patients and 172 healthy controls from the PPMI cohort. PD patients had a baseline BAG of 1.1 years, with fast-progressing patients exhibiting a BAG of 3.0 years, whereas slow-progressing patients resembled the BAG of healthy controls. Higher BAG was associated with more severe baseline symptoms, faster cognitive decline in several domains, increased hazard of developing mild cognitive impairment, and faster progression of dopaminergic neuron loss in longitudinal DaTSCANs. BAG-based patient stratification could reduce sample sizes of randomized clinical trials by 23-58%. These findings suggest BAG as a prognostic biomarker of disease progression, which may accelerate the development of disease-modifying treatments.
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