Objectives:It is unknown whether there are sex-related profiles of cardiometabolic health that contribute differently to age-related changes in brain health during midlife. We studied how latent classes of middle-aged individuals clustering by age, sex, menopause and cardiometabolic health were associated with brain structure and cognitive performance.Methods:Health, brain and abdominal magnetic resonance imaging (MRI) data from the UK Biobank cohort (men and women >40 years in the United Kingdom) were used. We applied latent class analysis to identify groups of individuals based on age, sex, menopausal status and cardiometabolic health. We examined associations of class membership with brain volumes (total brain [TBV], grey matter [GMV], white matter [WMV], hippocampal [HV], white matter hyperintensities [WMHV]) and cognitive performance.Results:Data were available for 36,420 individuals (mean age 64.9 years, 48.5% women). Eight latent classes differing in age, sex and cardiometabolic risk were identified. Class 1 (reference class) included individuals with the lowest probability of older age and cardiometabolic risk, and they had the most positive associations with cognitive function and brain volumes. In those aged >60, but not in those aged 50-60 years, the negative associations of age with TBV, GMV and WMV were greater in the class comprising healthier older women than classes comprising older men of varying cardiometabolic and vascular health. There were no age-class interactions for cognitive test performance.Conclusions:Latent class analysis detected groups of middle-aged individuals clustering by cardiometabolic health. The relationship of age with brain volumes varies by sex, menopausal status and cardiometabolic health profile.