Longitudinal analysis of 726 PD patients found that carriers of GBA1 PD-risk variants (and nominally severe variants) showed faster cognitive decline and, for PD-risk carriers, greater worsening of apathy, sleep, tremor, and non-motor symptom scores, though associations did not survive…

Links between GBA1 risk variants and accelerated non-motor progression reinforce lysosomal dysfunction as a therapeutically actionable axis and justify using GBA1 status for trial stratification or targeting, but the results are exploratory and need independent replication before clinical…

INTRODUCTION: An association between severe GBA1 variants and the progression of non-motor symptoms in PD has been reported, but the role of Parkinson's-risk (PD-risk) GBA1 variants is less clear. METHODS: We assessed symptom progression in individuals with severe and PD-risk variants compared to non-carriers. We analyzed longitudinal data from 726 individuals with typical PD, including 22 carriers of severe GBA1 variants and 47 carriers of PD-risk GBA1 variants. RESULTS: The findings were not significant after adjusting for Bonferroni correction; however, linear mixed models analyses showed that at a nominal significance level of 5%, carriers of PD-risk or severe variants were associated with faster cognitive decline compared to non-carriers. Moreover, carriers of PD-risk variants were associated with faster worsening of apathy, quality of sleep, tremor, and non-motor symptoms [Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS I)] compared to non-carriers; however, we did not observe this tendency in individuals with severe variants. DISCUSSION: The exploratory study suggests associations between PD-risk variants and a more rapid disease progression among carriers compared to non-carriers. Nevertheless, the findings should be interpreted cautiously and require confirmation in an independent cohort before any reevaluation of their pathologic relevance.