Associations of cholinergic system integrity with cognitive decline in GBA1 and LRRK2 mutation carriers

In Parkinson's disease (PD), GBA1- and LRRK2-mutations are associated with different clinical phenotypes which might be related to differential involvement of the cholinergic system. We investigated cholinergic integrity in 149 asymptomatic GBA1 and 169 asymptomatic LRRK2 mutation carriers, 112 LRRK2 and 60 GBA1 carriers with PD, 492 idiopathic PD, and 180 controls from the PPMI cohort. Basal forebrain volumes were extracted and white matter pathways from nucleus basalis of Meynert (NBM) to cortex and from pedunculopontine nucleus (PPN) to thalamus were assessed with a free water-corrected DTI model. Bayesian ANCOVAs were conducted for group comparisons and Bayesian linear mixed models to assess associations with cognitive decline. Basal forebrain volumes were increased in asymptomatic GBA1 (Bayes Factor against the null hypothesis (BF₁₀) = 75.2) and asymptomatic LRRK2 (BF₁₀ = 57.0) compared to controls. Basal forebrain volumes were increased in LRRK2- compared to GBA1-PD (BF₁₀ = 14.5) and idiopathic PD (BF₁₀ = 3.6*10⁷), with no difference between idiopathic PD and PD-GBA1 (BF₁₀ = 0.25). Mean diffusivity along the medial NBM pathway was decreased in asymptomatic GBA1 compared to controls (BF₁₀ = 30.3). Over 5 years, idiopathic PD and PD-GBA1 declined across all cognitive domains whereas PD-LRRK2 patients only declined in processing speed. We found an interaction between basal forebrain volume and time in predicting multiple cognitive domains in idiopathic PD and PD-GBA1, but not in PD-LRRK2. While LRRK2 and GBA1 mutations are both associated with increased basal forebrain volume at asymptomatic stages, this increase persists at the symptomatic PD stage only in LRRK2 and might be related to slower cognitive decline in these patients.