Neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Objective. We hypothesized that mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes will be associated with aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, while mutations associated with non-neuropathic GD will confer intermediate progression rates. Methods. 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. Results. 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HR) for global cognitive impairment of 3.17 (95% CI, 1.60 - 6.25) and a hastened decline in Mini Mental State Exam scores compared to non-carriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had HR of 3.22 (95% CI, 1.18 - 8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR of 1.96 (95% CI, 0.92 - 4.18)) or non-pathogenic risk variants (6.6% of patients; HR of 1.36 (95% CI, 0.89 - 2.05) did not reach significance. Interpretation. Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear”. These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline, and have direct implications for improving the design of clinical trials in PD. This article is protected by copyright. All rights reserved.