Objective: To characterize disease heterogeneity and how sex impacts motor and cognitive progression class membership across genetic subgroups of GBA1, LRRK2, and idiopathic Parkinson disease (PD).

Background: Autosomal dominant variants in GBA1 and LRRK2 account for approximately 10% of PD cases and are associated with different cognitive and motor trajectories. However, the role of sex in shaping progression within and across these genetic subgroups is not well understood.

Method: Longitudinal cohorts with 1867 PD (36% women), 393 GBA1 PD (44% women) and 638 LRRK2 PD (51% women) from Mount Sinai BI, MJFF-PPMI, PD Biomarker Program, and MJFF-LCC were analyzed. Growth mixture models characterized motor and cognitive trajectories using MDS-UPDRS Parts II and III and MoCA up to 20 years. Multinomial logistic regression identified factors associated with assigned class membership, adjusting for baseline age and cohort. Sex was a primary predictor alongside genetic status and olfaction.

Results: In overall analyses, female sex was broadly protective against faster motor and cognitive progression classes, with a stronger signal in GBA1 versus LRRK2. In LRRK2, the sex effect was limited to motor outcomes (MDS-UPDRS III OR=0.62, 95% CI 0.37-1.03), with no cognitive effect. In GBA1, female sex protected against fast motor progression (MDS-UPDRS III OR=0.52, 95% CI: 0.29-0.92) and lower risk for severe cognitive class (OR=0.56, 95% CI: 0.3-1.0). In sex-stratified analyses, among both women and men, GBA1 associated with faster functional motor decline (women MDS-UPDRS II OR=1.58, men OR=1.69), but its effect on cognition was markedly sex-dependent: GBA1 associated with faster cognitive decline in men (MoCA fast OR=3.94), but not women. LRRK2 showed comparable motor (women OR=0.43, men OR=0.45) and cognitive protection in both sexes. Hyposmia associated with faster cognitive decline in both sexes.

Conclusion: GBA1 genotype, especially, warrants consideration in trial design as it is both relatively frequent and associated with motor and cognitive progression trajectories. Female sex demonstrates association with better cognitive and motor classes overall in PD as well as within genetic cohorts. Depending on trial specifics including mechanism and outcome, both sex and genotype might merit integration into trial design. This includes the possibility of sex-stratified randomization or prespecified analyses accounting for sex differences.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/interplay-of-sex-and-gba1-and-lrrk2-genotype-in-parkinson-disease-progression/