Genetic Susceptibility to Cardio‐Cerebrovascular Diseases and White Matter Integrity in Asymptomatic Older Adults: A UK Biobank Observational Cohort Study

ABSTRACT Background Cardio‐cerebrovascular diseases are linked to neuroanatomical changes that may arise from genetic risk profiles, with structural brain alterations often preceding clinical onset. The pathways connecting genetic susceptibility to early neuroimaging phenotypes remain unclear. Purpose To examine the effects of polygenic risk for cardio‐cerebrovascular diseases (PRS CCVD ) on brain structure in healthy middle‐aged and older adults. Study Type Observational cohort study. Population 29,714 healthy White British individuals (mean age 54.86 ± 7.44 years; 13,691 male). Field Strength/Sequence 3T MRI; 3D‐MPRAGE T1, DTI (monopolar Stejskal‐Tanner). Assessment Brain structural measurements were derived from 48 white matter tracts (Johns Hopkins University atlas) using eight diffusion MRI metrics for white matter microstructure, and from 62 cortical regions (Desikan‐Killiany‐Tourville atlas) for cortical thickness and surface area measurements. Confirmatory factor analysis was applied to calculate the polygenic risk score for PRS CCVD based on PRS scores for cardiovascular disease, coronary artery disease, and ischemic stroke. Statistical Tests Associations between PRS CCVD and 508 brain structural MRI phenotypes were examined using multivariate linear regression with Bonferroni correction. Comparative analyses between gray and white matter phenotypes, as well as between older (≥ 60 years) and middle‐aged (< 60 years) participants, were performed using Wilcoxon signed‐rank tests ( p < 0.05). Propensity score matching was applied to balance covariates in age‐related effect analyses. Results PRS CCVD was significantly associated with 117 white matter ( β range: −0.042 to 0.051, partial R 2 range: 0.29% to 0.05%) and two cortical phenotypes (bilateral insular: β = −0.023, partial R 2 range: 0.05%–0.06%) in healthy middle‐aged and older adults. White matter microstructure was more vulnerable than cortical morphometry ( W = 37,912). Older adults had more severe white matter microstructure damage than the middle‐aged people ( W = 49,046). Data Conclusion PRS CCVD preferentially affects white matter microstructure over cortical morphometry in asymptomatic individuals, with exacerbated effects in older adults. Evidence Level 3. Technical Efficacy 2.