The composition of the cohorts, quality of the data, and the depth of proteome coverage allowed us to identify pathogenic LRRK2‐regulated lysosomal protein signatures that could serve as biomarkers to stratify subjects with pathogenic LRRK2. Taken together, our study offers evidence that quantitative MS‐based proteomics represents a clinically useful strategy for non‐invasive monitoring of disease progression and treatment response as well as patient stratification in PD. Here, LRRK2 is linked to Parkinson disease.