Objective: To investigate the longitudinal impact of MAOIs on motor progression among Parkinson’s disease (PD) patients carrying GBA1 mutations, with an emphasis on sex-stratified clinical outcomes.

Background: Mutations in the glucocerebrosidase gene (GBA1) are the most predominant genetic risk factor for PD, usually associated with a steep course leading to an early demented state. Monoamine oxidase-B inhibitors (MAOIs) were postulated to have a disease-modifying effect in some studies, but this was contradicted by others. While biological sex modulates PD progression and oxidative stress resilience, its effect on the response to MAOIs in GBA1 carriers remains unclear.

Method: A total of 259 PD patients (106 women, 153 men; 948 assessments) from Shaare Zedek Medical Center were included. Sixty-six (25.5%) were identified as GBA1 mutation carriers (30 women, 36 men), including 8 biallelic (Gaucher disease) subjects. Motor progression was evaluated using the MDS-UPDRS-III total and sub-domain scores. Longitudinal decline rates were calculated via Generalized Estimating Equations (GEE), adjusted for age at diagnosis. Statistical analysis was performed in Python (v3.12) with AI assistance (Gemini 3) for language editing.

Results: Over a mean clinical follow-up period of 1.68 ± 1.72 yrs (range: 0-5.47 yrs), MAOI use in the overall PD cohort was associated with a significantly slower annual rate of motor decline (Slope Difference: -0.95; P=0.031) [Table 1], with no sex-related difference in treatment response (P=0.414). Among GBA1 carriers, a sex-specific effect emerged: female carriers treated with MAOIs exhibited a notable trend toward slower motor progression, with a ~1 point/yr slower rate of MDS-UPDRS-III progression (Slope Difference: -0.971; P=0.078) [Table 2, figure 1&2]. Conversely, no protective effect was observed in male GBA1 carriers (Slope Difference: -0.070; P=0.919). Baseline motor severity and age were comparable between sexes in the GBA1 subgroup [Table 3].

Conclusion: Our findings suggest a potential sex-specific therapeutic window for MAOIs in GBA1-associated PD. Enhanced antioxidant capacity and dopaminergic compensation in women may interact with MAOIs to slow GBA1-driven neurodegeneration. These results highlight the importance of sex-stratified analyses in clinical trials and support further research into personalized therapeutic approaches for genetic variants of Parkinson’s disease.

Table 1

Table 2

Figure 1

Figure 2

Table 3

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