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. 2025 Mar 4;11(1):41.
doi: 10.1038/s41531-025-00883-7.

Male sex accelerates cognitive decline in GBA1 Parkinson's disease

Silvia Paola Caminiti  1 , Micol Avenali  2   3 , Alice Galli  4 , Rachele Malito  3 , Giada Cuconato  5 , Caterina Galandra  3 , Rosaria Calabrese  3 , Andrea Pilotto  4   6 , Alessandro Padovani  4   6 , Fabio Blandini  2   7 , Daniela Perani  8 , Cristina Tassorelli  2   3 , Enza Maria Valente  3   5
Affiliations

Male sex accelerates cognitive decline in GBA1 Parkinson's disease

Silvia Paola Caminiti et al. NPJ Parkinsons Dis. .

Abstract

We evaluated 128 GBA and 432 nonGBA Parkinson's disease (PD) subjects available from Parkinson's Progression Markers Initiative. Baseline clinical features and dopaminergic activity were assessed, together with clinical follow-up (6.87 ± 3.2 years). Survival analyses assessed the independent and interactive effects of sex and GBA1 mutations on cognitive decline. At baseline, GBA-PD males showed severe motor impairment, sleep disorders and memory deficits. Despite milder motor deficit, compared to GBA-PD males, GBA-PD females showed greater dopaminergic denervation, suggesting the effect of neural reserve. In longitudinal assessment, GBA-PD males showed greater MoCA rate of change per year and greater risk of cognitive impairment than GBA-PD females and nonGBA-PD. In GBA-PD males, both late age at onset and "severe/mild" GBA variants were associated with increased risk of cognitive impairment. Male sex and GBA1 carrier status have an additive value in increasing the risk of cognitive decline in PD. The effect of sex on GBA1-related pathology warrants further examination to address future trials design and patients' selection.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethical approval: Each PPMI participating site received approval from their local ethics committee before study initiation, and written informed consent was obtained from all participants before enrolment, in full compliance with the principles set out by the Declaration of Helsinki. We have obtained permission for publishing our research from the Data and Publication Committee of the PPMI study.

Figures

Fig. 1
Fig. 1. Dopaminergic uptake differences between groups.
a Significantly reduced dopamine binding in GBA-PD subjects compared to nonGBA-PD subjects, resulting from the voxel-wise regression model, adjusted for age at acquisition, Asymmetry Index, MDS-UPDRS-III and LEDD. b Violin plots representing the distribution of dopaminergic binding potentials among the four clinical and HC groups. c Box plots representing the distribution of neural reserve score among the four PD groups.
Fig. 2
Fig. 2. Survival curves for PD patients.
Kaplan-Meier curves showing the association between the probability of conversion to cognitive impairment, adjusted for age, disease duration, and education at baseline. The effects estimated include: (a) biological sex; (b) GBA1 carrier status; (c) age at symptoms onset (AAO); (d) interaction between GBA1 genotype and biological sex; (e) interaction between biological sex and AAO; and (f) interaction between GBA1 carrier status and AAO.
See this image and copyright information in PMC

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