LAUSR

Background The brain-age-gap estimate (brainAGE) quantifies the difference between chronological age and age predicted by applying machine-learning models to neuroimaging data, and is considered a biomarker of brain health. Understanding sex-differences in brainAGE is a significant step toward precision medicine. Methods Global and local brainAGE (G-brainAGE and L-brainAGE, respectively) were computed by applying machine learning algorithms to brain structural magnetic resonance imaging data from 1113 healthy young adults (54.45% females; age range: 22-37 years) participating in the Human Connectome Project. Sex-differences were determined in G-brainAGE and L-brainAGE. Random forest regression was used to determine sex-specific associations between G-brainAGE and non-imaging measures pertaining to sociodemographic characteristics and mental, physical, and cognitive functions. Results L-brainAGE showed sex-specific differences in brain ageing. In females, compared to males, L-brainAGE was higher in the cerebellum and brainstem and lower in the prefrontal cortex and insula. Although sex-differences in G-brainAGE were minimal, associations between G-brainAGE and non-imaging measures differed between sexes with the exception for poor sleep quality, which was common to both. The most important predictor of higher G-brainAGE was non-white race in males and systolic blood pressure in females. Conclusions The results demonstrate the value of applying sex-specific analyses and machine learning methods to advance our understanding of sex-related differences in factors that influence the rate of brain ageing and provide a foundation for targeted interventions.