BACKGROUND: Amyloid precursor-like protein 1 (APLP1) is involved in pathological α-synuclein transmission, but its role in Parkinson's disease (PD) progression has not been explored. OBJECTIVE: This study investigates APLP1 as a potential predictor for motor and cognitive deterioration in PD. METHODS: Plasma APLP1 levels were measured in PD patients from the Huashan Hospital for Parkinson's Disease (HSPD) and Parkinson's Disease Progression Markers Initiative (PPMI) cohorts. A total of 916 participants were recruited in the HSPD cohort, and 171 participants were in the PPMI cohort. Longitudinal analysis examined the association between baseline APLP1 levels and PD progression. RESULTS: A significant increase in APLP1 levels was observed in PD patients compared to healthy controls. Longitudinal analysis showed that patients with elevated baseline APLP1 levels experienced faster motor deterioration in HSPD cohort (HR = 3.627, P <
0.0001). CONCLUSIONS: The data indicate that APLP1 is associated with the progression of PD, potentially offering a measurable indicator of disease progression. © 2025 International Parkinson and Movement Disorder Society.