Sex-Specific Association of Rasagiline with Motor Progression in GBA1-Associated Parkinson's Disease

Variants in the glucocerebrosidase gene (GBA1) are the predominant genetic risk factor for Parkinson's disease (PD), often accelerating disease progression. While biological sex modulates PD progression, the longitudinal association between rasagiline (a monoamine oxidase-B [MAO-B] inhibitor) and motor outcomes in GBA1-associated Parkinson's disease (GBA1-PD) remains unclear. This retrospective cohort study (2019-2026) analyzed 259 patients with PD (106 females, 153 males) with a median follow-up of 1.56 years to evaluate the association between rasagiline use and motor decline, emphasizing sex-stratified outcomes. Motor progression was evaluated using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III). Rates of change were calculated using sex-stratified Generalized Estimating Equations models, with adjustment for age at diagnosis to evaluate treatment effects and sex-specific associations. Among 259 patients, rasagiline use was associated with a significantly slower annual rate of motor decline (Slope Difference: -0.95; p = 0.03). In the GBA1-PD subgroup, females using rasagiline exhibited a clinically relevant slower rate of progression (approximately 1 point/year on the MDS-UPDRS-III) compared with non-users, although not statistically significant (p = 0.08); no association was observed in males. These findings suggest a potential sex-specific association of rasagiline with motor progression in GBA1-PD. Results highlight the importance of sex-stratified analyses to support personalized therapeutic approaches for PD genetic variants.