Understanding the Pattern of Cognitive Decline in GBA1-Related Parkinson's Disease: An Exploratory Longitudinal Multi-Cohort Study

People with Parkinson's disease (PD) who carry a pathogenic GBA1 variant (PD_GBA1) are at higher risk of cognitive impairment than those without the variant (PD_{GBA1_wildtype}). To date, little is known about the pattern and evolution of cognitive decline in PD_GBA1. This multicenter study characterized the cognitive profile of PD_GBA, focusing on the longitudinal trajectories and the group-specific onset times among cognitive functions, as well as their clinical relevance.

In this exploratory longitudinal multicohort-study (Parkinson's Precision Medicine Initiative [PPMI], Amyloid-Beta in cerebrospinal spinal fluid as a risk factor for cognitive dysfunction in Parkinson's Disease [ABC-PD], and National Centre for Excellence in Research on Parkinson's disease [NCER-PD]), comprehensive neuropsychological assessments were standardized across 546 healthy controls (follow-up years = 2.9 ± 4.3), 903 PD_{GBA1_wildtype} (follow-up years = 4.4 ± 4.2), and 211 PD_GBA1 (follow-up years = 4.8 ± 3.4). We evaluated performance across age and disease duration using generalized linear mixed effects models (GLMMs) within each cognitive domain. An exploratory latent trajectory analysis was computed to identify potential cognitive subgroups. Time-to-first-event models, assessing risks of clinically relevant performance impairment (test score z ≤ -1.5, Montreal Cognitive Assessment [MoCA] < 26), and an expanding time-window approach identified the course of cognitive impairment.

PD_GBA1 performed worse in executive function, attention, visuocognitive skills, and memory than PD_{GBA1_wildtype} at baseline and exhibited a more rapid and widespread decline across these domains. The risk of developing clinically relevant cognitive impairment during the disease course was increased in PD_GBA1. Processing speed and visuoperceptual showed the earliest performance impairments in PD_GBA1, preceding PD_{GBA1_wildtype} by 1.2 and 2.5 disease years, respectively. Within the PD_GBA1 group, we identified a subgroup with rapidly declining cognition, who were more likely to be male patients, report depressive symptoms, and carry a severe GBA1 mutation.

PD_GBA1 exhibits accelerated domain-generalized and more severe cognitive decline compared to PD_{GBA1_wildtype}. ANN NEUROL 2026.