Combined detrimental effect of male sex and GBA1 variants on cognitive decline in Parkinson’s Disease

Heterozygous variants in the glucocerebrosidase gene (GBA1) are the major genetic risk factor for Parkinson’s Disease (PD). GBA-PD has been associated with worse progression and higher risk of cognitive decline. Here we took advantage of the Parkinson’s Progression Markers Initiative (PPMI) to investigate whether sex could interact with GBA1 carrier status in determining the clinical phenotype, with a special focus on cognitive decline. Heterozygous variants in the glucocerebrosidase gene (GBA1) are the major genetic risk factor for Parkinson’s Disease (PD). GBA-PD has been associated with worse progression and higher risk of cognitive decline. Here we took advantage of the Parkinson’s Progression Markers Initiative (PPMI) to investigate whether sex could interact with GBA1 carrier status in determining the clinical phenotype, with a special focus on cognitive decline. Regardless of genotype, men suffering from PD exhibited higher motor disability while women showed more autonomic dysfunction. At baseline, GBA-PD showed more severe motor and non-motor features, and reduced dopamine uptake in the bilateral ventral putamen compared to nonGBA-PD. Within the GBA-PD group, males had higher occurrence of REM sleep behavior disorder and memory deficits. Of note, GBA-PD females showed a greater striatal dopaminergic deficit compared to males, despite presenting similar motor impairment. In longitudinal assessment, Cox Regression revealed that male sex (HR = 1.7), GBA1 carrier status (HR =1.6) and, most importantly, GBA-by-male sex interaction (HR = 2.3) were significantly associated with a steeper cognitive decline. Upon stratification for GBA1 variant class, both “severe” and “mild” variants were associated with increased risk of cognitive decline, again more relevant in males (HR = 2.3). We show, for the first time, that male sex and GBA1 carrier status have an additive value in increasing the risk of cognitive decline in PD, despite the heightened dopaminergic vulnerability observed in GBA-PD females. The effect of sex on GBA1-related pathology warrants further examination and should be considered in future trials design and patients’ selection.