Cholinergic Degeneration and Cognitive Function in Early GBA1‐Related Parkinson's Disease

Objective The phenotype of patients with Parkinson's disease carrying GBA 1 variants (GBA‐PD) suggest similarities to symptomatology associated with early cholinergic system degeneration. Therefore, this study aims to investigate the clinical features and the cholinergic innervation pattern in patients with early GBA‐PD versus those without the GBA1 mutation (non‐GBA‐PD). Methods A total of 46 GBA‐PD and 104 non‐GBA‐PD subjects were included. Clinical assessments included motor and non‐motor evaluation, as well as a comprehensive neuropsychological examination. Cholinergic system integrity was assessed using 1 8 F‐Fluoroethoxybenzovesamicol ( 18 F‐FEOBV) positron emission tomography (PET) to investigate the differences between GBA‐PD and non‐GBA‐PD. Given the higher prevalence of females in GBA‐PD, analyses were repeated when stratified by sex. Additionally, we examined the association between cognitive domains and whole‐brain cholinergic binding in both groups. Exploratory analyses examined clinical and 18 F‐FEOBV binding differences among GBA1 variants. Results GBA‐PD patients exhibited a higher burden of non‐motor symptoms and lower cognitive performance on executive functions and attention. We observed a more pronounced cholinergic denervation in GBA‐PD, compared to non‐GBA‐PD, primarily in the anterior, central, and limbic regions. However, the distribution of cholinergic loss and its association with attention and executive dysfunction was comparable between GBA‐PD and non‐GBA‐PD. In addition, the clinical presentation and cholinergic binding differed significantly between sexes. Interpretation These results suggest an important role of early cholinergic denervation in GBA‐PD patients, which is related to more severe cognitive dysfunction. ANN NEUROL 2025;98:398–409