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

Background and Objective: 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. Methods: We evaluated 118 PD subjects carrying GBA1 variants (GBA-PD) and 450 with wild-type alleles (nonGBA-PD) included in the PPMI. Dopaminergic activity was assessed in a subset of 248 subjects (65%) with available 123I-FP-CIT SPECT scans. Clinical features and dopaminergic activity were investigated in GBA-PD vs. nonGBA-PD groups, upon stratification by sex. PD subjects were followed for up to 6.5 years (median 6 years). Cox regression was used to model the hazard ratio (HR) of (1) GBA1 genotype, (2) sex, (3) gene-by-sex interaction on cognitive decline at follow-up. Results: 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). Discussion: 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. ### Competing Interest Statement The authors report no disclosures relevant to the manuscript. Outside the submitted work, SPC is supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006), a multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). CT has received personal fees for participating in advisory boards for Eli Lilly. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used in the preparation of this article were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit www.ppmi-info.org I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.