Introduction: Cerebrovascular disease (CVD) and vascular risk factors cluster in families of patients with early-onset coronary artery disease (CAD). In a prior cross-sectional study of 714 healthy middle-aged relatives, we found a high prevalence of early white matter hyperintensity lesions (WMHL) and associated lower cognitive function. Prior WMHL studies have included elderly or demented subjects. Rate of WMHL progression and cognitive decline in quiescent preclinical healthy middle-aged persons remains unknown. Methods: We studied WMHL and cognitive function over 5 years in 20 healthy relatives, age 50-59, of patients with CAD <60 years of age (one subject per family). Persons with any physical or neurological abnormality were excluded. At baseline and follow-up, subjects underwent 3-Tesla brain magnetic resonance imaging. WMHL volumes were determined using automated segmented volumes measured from FLAIR and MPRAGE using a previously described automated pipeline. Cognitive function was measured with the: Delayed Recall, Digit Symbol Substitution, Verbal Fluency, Digit Span, and Grooved Pegboard tests. Results: Our 20 participants were: 50% male, 45% African American (AA), average age was 54.1 (SD 1.57) years, 45% with HTN, 15% smokers, and 50% obese. WMHL prevalence was 92%. The average change in WMHL volume was 819 mm 3 (P<0.0008); this was significant for men (p=0.006), women (p= 0.062), AAs (p= 0.019), and European Americans (EA) (p= 0.018). Decline occurred in all cognitive function tests (average P across all tests was <0.001) in all races and sexes. Vascular risk factors did not change from baseline to follow-up. Conclusion: These striking findings are among the first to demonstrate significant quantitative WMHL volume progression and cognitive decline in a healthy middle-aged population over just 5 years, in AA and EA and both sexes. This small pilot study suggests that early quiescent brain white matter lesion progression and early multidimensional cognitive decline can be detected in healthy susceptible populations using state-of-the-art quantitative volumetric imaging techniques.