Clinical and neuropsychological characterisation of GBA1-associated Parkinson’s Disease: a cross-sectional and longitudinal analysis

Parkinson’s disease (PD) is a neurodegenerative disorder characterised by heterogeneous motor and non-motor manifestations. Genetic factors, such as GBA1 mutations, represent major contributors to this variability and are associated with distinct clinical phenotypes and accelerated cognitive decline. Despite growing recognition of the role of GBA1 variants, the neuropsychological profile of mutation carriers, especially across time, and its relationship with variant severity and disease duration remain incompletely understood. The aim of this study was to provide a comprehensive clinical characterisation of the cognitive profile of PD patients carrying GBA1 variants (GBA-PD) compared with non-mutated PD (NM-PD), Specifically, we investigated baseline cognitive differences, longitudinal trajectories, and the impact of variant severity and disease duration on both clinical and neuropsychological outcomes. A cohort of 118 PD patients underwent extensive neuropsychological testing at baseline and across longitudinal follow-up assessments. Subgroup analyses stratified carriers by variant severity (GBA1 severe vs non-severe) and disease duration [early (D-) vs advanced (D+)]. Group comparisons were assessed using non-parametric tests, whereas longitudinal changes were evaluated by estimating individual slopes with linear regression and by linear mixed-effects models with random intercepts and slopes, adjusted for demographic covariates. Neuropsychological scores were standardized to normative data (residual scores or z-scores adjusted for age and, where applicable, education), ensuring comparability across individuals. At baseline, between-group differences were limited, with phonological fluency emerging as the only feature consistently distinguishing carriers from non-carriers across all stratifications. Noteworthily, longitudinal analyses revealed a clearer divergence: GBA-PD patients exhibited progressive decline in visuospatial memory, attentional processing and executive control, whereas NM-PD remained comparatively stable. In GBA-PD, cognitive decline was most pronounced in carriers of severe GBA1 variants, supporting a severity-dependent gradient of cognitive vulnerability. Stratification by disease-duration confirmed expected differences in dopaminergic treatment, as well as reinforcing that genetic status independently influenced cognitive outcomes. In summary, GBA-PD shows a distinct cognitive profile characterised by accelerated decline in executive, visuospatial and attentional domains. Cognitive trajectories are mainly driven by genetic status and variant severity, with disease duration contributing secondarily to overall burden.