The interplay between GBA1 status and age of onset on cognitive, motor and non-motor outcomes in Parkinson’s disease: multicenter cross-sectional study

BACKGROUND AND OBJECTIVES: Age at onset is a key determinant of disease course in the general Parkinson's disease (PD) population, but its influence among GBA-PD remains undetermined. This study investigates whether age at onset affects cognitive decline in GBA-PD patients and compares symptoms between GBA-PD and nonGBA-PD groups, stratified by age of onset. METHODS: In this multicentric cross-sectional study, PD patients were stratified into early onset (< 50 years), intermediate onset (50-60 years), and late onset (> 60 years). Demographic-clinical data and scores of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT), and Beck Depression Inventory (BDI-II) were compared using ANCOVA. The effects of age of onset, GBA1 status, and their interaction were investigated. External validation on cognition was performed using data from the PPMI cohort. RESULTS: We analyzed 80 GBA-PD and 236 nonGBA-PD patients. Among GBA-PD, late-onset patients exhibited worse axial scores (p = 0.037), while early-onset had more severe motor complications (p = 0.007) and dysautonomia (p = 0.012). Age of onset and GBA1 status did not influence MoCA scores. Conversely, GBA1 status independently affected MDS-UPDRS parts I and II (p < 0.001 and p = 0.019, respectively) and BDI-II scores (p = 0.002). Analysis on the external dataset (PPMI) showed late-onset PD had lower MoCA scores (p < 0.001) and confirmed GBA1 status did not influence cognition. DISCUSSION: In the first decade of PD, cognitive decline is mainly age and duration dependent, irrespective of GBA1 genotype. Early onset does not increase cognitive risk in GBA-PD, supporting its relevance for counseling and treatment planning.