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

## TL;DR

This study explores how age at onset and GBA1 gene status affect symptoms in Parkinson’s disease patients, finding that cognitive decline is more influenced by age than genetic factors.

## Contribution

The study is the first to show that cognitive decline in Parkinson’s disease is primarily age-dependent, not influenced by GBA1 status.

## Key findings

- Late-onset GBA-PD patients had worse axial scores and early-onset had more motor complications and dysautonomia.
- GBA1 status affected motor and non-motor symptoms but not cognitive scores.
- Cognitive decline in Parkinson’s disease is mainly influenced by age and disease duration, not GBA1 genotype.

## Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1007/s00415-026-13639-x.