Progression of GBA1 severe and risk variants: a longitudinal mixed model analysis

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.