Impact of GBA variants on longitudinal freezing of gait progression in early Parkinson’s disease

Background Freezing of gait (FOG) is a common disabling gait disturbance among patients with Parkinson’s disease (PD), but the influence of genetic variants on the incidence of FOG has been poorly studied to date. Objectives We aimed to evaluate the association of GBA variants with the risk of FOG development in a large early PD cohort. Methods This study included 371 early PD patients from the Parkinson’s Progression Markers Initiative (PPMI) who were divided into a GBA variant carrier group (GBA-PD group, n = 44) and an idiopathic PD group without GBA variants (iPD group, n = 327). They were followed up for up to 5 years to examine the progression of FOG. The cumulative incidence of FOG and risk factors for FOG were assessed using Kaplan‒Meier and Cox regression analyses. Results At baseline, the GBA-PD group had lower CSF β-amyloid 1–42 (Aβ 42 ) levels and more severe motor and nonmotor symptoms than the iPD group. During the 5-year follow-up, the GBA-PD group had a higher incidence of FOG than the iPD group, and the FOG progression rate was related to GBA variant severity. In the multivariable Cox model without CSF Aβ 42 , GBA variants were significant predictors of future FOG, and the association remained significant after adding CSF Aβ 42 to the model. In the subgroup analyses, the effect of GBA variants was not observed in the “low-level” group. However, in the “high-level” group, GBA variants independently increased the risk of FOG, and this association was stronger than the association with CSF Aβ 42 . Conclusion GBA variants are novel genetic risk factors for future FOG development in early PD patients. This association seemed to be mediated by both Aβ-dependent pathways and Aβ-independent pathways.