Circulating branched-chain amino acids and multimodal signatures of incident Parkinson’s disease: a prospective cohort study

The role of circulating branched-chain amino acids (BCAAs) in Parkinson’s disease (PD) remains unclear. We investigated the association between plasma BCAAs and incident PD and characterized their prediagnostic patterns and related biological signatures in 374,751 UK Biobank participants free of PD and other neurodegenerative diseases at baseline. Cox proportional hazards models were used to estimate associations of total BCAAs, leucine, isoleucine, and valine with incident PD. Restricted cubic splines assessed dose-response relationships, and LOESS smoothing modeled control-standardized pseudotemporal patterns of baseline BCAA levels according to time to PD diagnosis. Fully adjusted linear regression models evaluated associations of BCAAs with PD-related plasma protein biomarkers, PhenoAge acceleration, and diffusion MRI-derived white matter microstructure. Higher circulating levels of total BCAAs, leucine, and valine were associated with lower incident PD risk, with approximately linear inverse dose-response relationships. Baseline BCAA levels were lower among participants assessed at time points closer to subsequent PD diagnosis. Higher BCAA levels were also associated with lower PhenoAge acceleration, lower GFAP and NEFL levels, and more favorable white matter microstructural profiles. These findings suggest that altered BCAA metabolism may represent a prediagnostic metabolic feature of PD and support further investigation of its biological and translational relevance.