In a propensity-matched PPMI cohort, LRRK2-PD patients who are alpha-synuclein SAA-positive had lower baseline motor scores and dopaminergic deficit than S+ sporadic PD, but showed similar 4-year clinical progression trajectories.

Shows that alpha-synuclein SAA stratification identifies a biologically relevant subgroup and indicates S+ LRRK2-PD progresses similarly to S+ sporadic PD, informing biomarker-driven trial design, patient selection, and outcome measures for LRRK2- or alpha-synuclein-targeted therapeutics.

BACKGROUND: LRRK2-Parkinson's disease (LRRK2-PD) is biologically heterogeneous with approximately 30% lacking aggregated alpha synuclein (αSyn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). OBJECTIVE: We aimed to assess how LRRK2-PD with αSyn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. METHODS: Data from the Parkinson's Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. RESULTS: At baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. CONCLUSIONS: Longitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.