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

Objective

People with Parkinson's disease (PD) who carry a pathogenic GBA1 variant (PDGBA1) are at higher risk of cognitive impairment than those without the variant (PDGBA1_wildtype). To date, little is known about the pattern and evolution of cognitive decline in PDGBA1. This multicenter study characterized the cognitive profile of PDGBA, focusing on the longitudinal trajectories and the group-specific onset times among cognitive functions, as well as their clinical relevance.

Methods

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 PDGBA1_wildtype (follow-up years = 4.4 ± 4.2), and 211 PDGBA1 (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.

Results

PDGBA1 performed worse in executive function, attention, visuocognitive skills, and memory than PDGBA1_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 PDGBA1. Processing speed and visuoperceptual showed the earliest performance impairments in PDGBA1, preceding PDGBA1_wildtype by 1.2 and 2.5 disease years, respectively. Within the PDGBA1 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.

Interpretation

PDGBA1 exhibits accelerated domain-generalized and more severe cognitive decline compared to PDGBA1_wildtype. ANN NEUROL 2026.