Sex-dependent dopaminergic vulnerability may contribute to sex differences in Parkinson’s disease risk

Abstract

Men are more likely than women to develop Parkinson’s disease (PD), yet the biological basis of this sex difference in PD risk remains unresolved. The nigrosome-1 (NG-1), a dopaminergic subregion of the substantia nigra, is selectively vulnerable to degeneration and iron accumulation in PD, therefore representing a plausible locus for sex-linked vulnerability. Using iron-sensitive magnetic resonance imaging from the UK Biobank, we examined sex differences in NG-1 magnetic susceptibility across adulthood.

We analysed cross-sectional data from 53,792 individuals aged 45–85 years and longitudinal follow-up in 4,068 participants. Across mid-to-late adulthood, men consistently exhibited higher NG-1 magnetic susceptibility than women, suggestive of greater iron-related signal burden. In contrast, age-related trajectories and rates of within-person change were similar between sexes, with no evidence for accelerated nigrostriatal ageing in men. Sensitivity analyses showed that these sex differences were not substantially modified by genetic risk for PD, cardiometabolic disease, or major lifestyle factors.

Together, these findings suggest that sex differences in NG-1 susceptibility are expressed primarily as a stable baseline offset rather than divergent ageing dynamics. By distinguishing baseline variation from age-related changes in a selectively vulnerable dopaminergic system, this study provides population-scale evidence relevant to understanding sex differences in vulnerability to PD.