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The American Heart Association (AHA) Life's Simple 7 (LS7) score captures 7 biological and lifestyle factors associated with promoting cardiovascular health.To test whether healthier LS7 profiles are associated with significant brain health benefits in persons without stroke or dementia, and to evaluate whether genomic information can recapitulate the observed LS7.This genetic association study was a nested neuroimaging study within the UK Biobank, a large population-based cohort study in the United Kingdom. Between March 2006 and October 2010, the UK Biobank enrolled 502 480 community-dwelling persons aged 40 to 69 years at recruitment. This study focused on a subset of 35 914 participants without stroke or dementia who completed research brain magnetic resonance imaging (MRI) and had available genome-wide data. All analyses were conducted between March 2021 and March 2022.The LS7 (blood pressure, low-density lipoprotein cholesterol, hemoglobin A1c, smoking, exercise, diet, and body mass index) profiles were ascertained clinically and genomically. Independent genetic variants known to influence each of the traits included in the LS7 were assessed. The total LS7 score ranges from 0 (worst) to 14 (best) and was categorized as poor (≤4), average (4 to 9) and optimal (9).The outcomes of interest were 2 neuroimaging markers of brain health: white matter hyperintensity (WMH) volume and brain volume (BV).The final analytical sample included 35 914 participants (mean [SD] age 64.1 [7.6] years; 18 830 [52.4%] women). For WMH, compared with persons with poor observed LS7 profiles, those with average profiles had 16% (β = -0.18; SE, 0.03; P .001) lower mean volume and those with optimal profiles had 39% (β = -0.39; SE, 0.03; P .001) lower mean volume. Similar results were obtained using the genomic LS7 for WMH (average LS7 profile: β = -0.06; SE, 0.014; P .001; optimal LS7 profile: β = -0.08; SE, 0.018; P .001). For BV, compared with persons with poor observed LS7 profiles, those with average LS7 profiles had 0.55% (β = 0.09; SE, 0.02; P .001) higher volume, and those with optimal LS7 profiles had 1.9% (β = 0.14; SE, 0.02; P .001) higher volume. The genomic LS7 profiles were not associated with BV.These findings suggest that healthier LS7 profiles were associated with better profiles of 2 neuroimaging markers of brain health in persons without stroke or dementia, indicating that cardiovascular health optimization was associated with improved brain health in asymptomatic persons. Genomic information appropriately recapitulated 1 of these associations, confirming the feasibility of modeling the LS7 genomically and pointing to an important role of genetic predisposition in the observed association among cardiometabolic and lifestyle factors and brain health.