Objective: To assess the impact of sex and glucocerebrosidase (GBA) mutations on cognitive trajectories in a sample of Parkinson’s disease (PD) patients.

Background: Accumulating evidence indicates that sex influences disease susceptibility, pathogenesis, and clinical presentation of PD. PD females show a late disease onset with mild motor symptoms and a more benign phenotype than males. Among the genetic factors, GBA mutations are considered one of the most important candidate risk factors for cognitive decline in PD. Both genotype and sex might have a combined effect on PD clinical trajectories.

Method: We analyzed data obtained from the Parkinson’s Progression Markers Initiative (PPMI) database, which included 478 PD patients (57.7% males), 72 (15%) GBA-related PD (GBA-PD; 51.4% males) carriers and 406 non-carrier PD patients (idiopathic, IPD; 58.9% males). Clinical features were compared between males and females separately for GBA mutation, and between IPD and GBA-PD separately for sex. Linear mixed-effects regression model was applied to evaluate sex-specific effects of the GBA status on the cognitive trajectories (MoCA scores obtained at baseline and at 1-10 years follow-up visits). Age, disease duration, education and their interaction with time were entered as random effects.

Results: p.N370S variant was the most prevalent GBA-variant (65% of patients). Among IPD, males had higher education levels (p<0.001) and lower disease duration (p<0.001) than females. Among GBA-PD, males showed steeper annual decline in MoCA scores (p=0.012) than females. Among same sex, females GBA-PD showed worse UPDRS-III (p=0.012), H&Y (p=0.008) and higher disease duration (p<0.001) than IPD; while GBA-PD males showed worse UPDRS-III (p=0.032), H&Y (p=0.049), and higher annual decline in MoCA scores (p<0.001) and disease duration (p<0.001) than IPD. According to linear mixed models, a faster rate of annual score decrease was found for males (β, −1.25; 95% CI, -1.88/−0.62; P < 0.001) and GBA-PD (β, −0.78; 95% CI, −1.24/−0.32; P = 0.001). We also found an interaction between mutation and sex, meaning that GBA-PD males declined faster than females GBA–PD and IPD patients (β, 0.75; 95% CI, 0.09/1.42; P = 0.026).

Conclusion: The results support that both GBA mutations and sex drive phenotype, with GBA-PD males characterized by a more malignant trajectory. The modulation of sex on genotype can be considered for future trial selection.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-sex-on-the-association-between-gba-mutations-and-cognitive-decline-in-parkinsons-disease/