Introduction: Subclinical brain disease manifested as white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) are putatively due to microvascular ischemic damage based on correlations with autopsy specimens. Because the vascular architecture of white matter differs in the subcortical (SC) and periventricular (PV) region, we hypothesized that the vasculopathic effects of aging will be differential by brain regions. We therefore studied the association of age with the ratio of SC to total WMH volume (SC/T ratio) in individuals at risk for premature cardiovascular disease. Methods: We enrolled 593 asymptomatic family members of probands with premature coronary artery disease (<60 years). The location and volume of WMH was determined from 3T cranial MRI using automated software. WMH was considered PV if it was confluent with the ventricles, and SC otherwise. The non-linear association of age with Laplace-smoothed SC/T ratio was examined using spline generalized estimating equation regression adjusted for sex, race and familial correlations. Results: Participants were 58% women, 37% African-American, aged 29-74 years. The figure shows that the median SC/T ratio was relatively larger and stable during the younger decades, while it was successively smaller in later decades. The non-linearity was best modeled using a linear spline at 56 years of age. The slope of SC/T ratio with respect to age was 0.0% (p=0.94) for age ≤ 56, but for age > 56, 1.4% lower per year of age (p<0.001). Conclusions: This is the first study showing that SC/T WMH ratio is high in younger adults at high familial cardiovascular risk. This finding suggests that subclinical premature vascular pathology at ages ≤ 56 years is predominantly SC. This differs from the aging-dependent pathology at ages > 56 years, which is predominantly non-SC, thus reducing the SC/T ratio at older ages.