Low-Density Lipoprotein Cholesterol Is Independently Associated with White Matter Injury Beyond Coronary Artery Calcium: Insights into Brain Aging

Background/Objectives: The interplay between cardiovascular risk factors and brain aging remains incompletely understood. We aimed to investigate the comparative associations of coronary artery calcium (CAC) and low-density lipoprotein cholesterol (LDL-C) with MRI-derived volumetric measures of the brain. Methods: In this retrospective, single-center, cross-sectional study, 84 participants who underwent coronary computed tomography for CAC scoring and brain magnetic resonance imaging within 90 days were included; LDL-C levels were available in 69 participants for LDL-based analyses. Brain volumetric measures were obtained using the automated lesionBrain pipeline within the volBrain platform, which performs fully automated tissue segmentation and lesion quantification based on multi-atlas and patch-based approaches. Associations were evaluated using Spearman’s correlation with false discovery rate correction and hierarchical multivariable regression, supported by bootstrap validation and post hoc power analysis. The cohort had a mean age of 58.0 ± 13.0 years (range 19–78) and was derived from routine clinical imaging. Results: LDL-C was positively associated with abnormal white matter volume (ρ = 0.334, p = 0.005), although this did not remain statistically significant after FDR correction (pFDR = 0.090). In fully adjusted models, LDL-C remained the only independent predictor (β = 0.006, 95% CI: 0.002–0.010, p = 0.007; standardized β = 0.225; partial R2 = 11.7%), corresponding to a 6.2% increase in abnormal white matter volume per 10 mg/dL increase (derived from log-transformed models). CAC showed only a marginal association (p = 0.059). Post hoc power analysis demonstrated adequate power for LDL-C but insufficient power for CAC. Neither marker was associated with gray matter volume. Conclusions: In this cross-sectional cohort, higher LDL-C was independently associated with greater abnormal white matter volume after adjustment for cardiovascular risk factors, statin use, and CAC. No CAC–brain association was detected in this cohort, but limited statistical power means that small CAC effects cannot be excluded. These findings should be interpreted as associative rather than causal or mechanistic.