Understanding the pattern of cognitive decline in GBA1-related Parkinson’s Disease: a 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 multi-center 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 longitudinal multicohort-study (PPMI, ABC-PD, Luxembourg Parkinson’s Study), comprehensive neuropsychological assessments were standardized across 548 healthy controls (follow-up-years=2.84±4.33), 906 PDGBA1_wildtype (follow-up-years=4.29±4.16), and 210 PDGBA1 (follow-up-years=4.09±3.35). We evaluated performance across age and disease duration using regression (generalized) linear mixed models within each cognitive domain. Time-to-first-event models, assessing risks of clinically relevant performance impairment (test-score z≤-1.5, MoCA<26), and an expanding-time-window approach identified the course of cognitive impairment. Additionally, correlations between cognitive functions were calculated. __Results__ At baseline, PDGBA1 showed lower performance in attention (processing speed) and memory (verbal learning) than PDGBA1_wildtype, but more widespread probability of performance impairment. Over time, attention, visuoperception, memory, and semantic fluency performance declined more rapidly in PDGBA1 compared to PDGBA1_wildtype. Impairment in processing speed occurred earlier in the disease process of PDGBA1. Risks for clinically relevant cognitive impairment in PDGBA1 during the disease course were generally increased. Moderate-to-strong correlations between cognitive functions were observed within and across cognitive domains in PDGBA1 and PDGBA1_wildtype, particularly in attentional-executive functions. __Interpretation__ PDGBA1 exhibits accelerated domain-generalized cognitive decline compared to PDGBA1_wildtype, with susceptibility of semantic fluency, attention, and memory.