Importance Identifying brain regions associated with risk factors for dementia could guide mechanistic understanding of risk factors associated with Alzheimer disease (AD). Objectives To characterize volume changes in brain regions associated with aging and modifiable risk factors for dementia (MRFD) and to test whether volume differences in these regions are associated with cognitive performance. Design, Setting, and Participants This cross-sectional study used data from UK Biobank participants who underwent T1-weighted structural brain imaging from August 5, 2014, to October 14, 2016. A voxelwise linear model was applied to test for regional gray matter volume differences associated with aging and MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use). The potential clinical relevance of these associations was explored by comparing their neuroanatomical distributions with the regional brain atrophy found with AD. Mediation models for risk factors, brain volume differences, and cognitive measures were tested. The primary hypothesis was that common, overlapping regions would be found. Primary analysis was conducted on April 1, 2018. Main Outcomes and Measures Gray matter regions that showed relative atrophy associated with AD, aging, and greater numbers of MRFD. Results Among 8312 participants (mean [SD] age, 62.4 [7.4] years; 3959 [47.1%] men), aging and 4 major MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use) had independent negative associations with specific gray matter volumes. These regions overlapped neuroanatomically with those showing lower volumes in participants with AD, including the posterior cingulate cortex, the thalamus, the hippocampus, and the orbitofrontal cortex. Associations between these MRFD and spatial memory were mediated by differences in posterior cingulate cortex volume (β = 0.0014; SE = 0.0006; P = .02). Conclusions and Relevance This cross-sectional study identified differences in localized brain gray matter volume associated with aging and MRFD, suggesting regional vulnerabilities. These differences appeared relevant to cognitive performance even among people considered cognitively healthy.