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Introduction: White matter tract disruption (WMTD) on Diffusion Tensor Imaging (DTI) may reflect early axonal disruption and tract injury and identify risk for dementia. Brain ceramides play a role in processes also associated with dementia risk. We hypothesized that circulating ceramide levels might serve as biomarkers of WMTD in a population at high risk for early vascular disease. We studied six ceramides and WMTD using fractional anisotropy (FA) on DTI in healthy relatives of patients with early coronary disease. We have previously shown a high prevalence of white matter hyperintensities (WMH) and significant associations between WMH volumes, FA, and lower cognitive function in healthy relatives.Methods: DTI was acquired with Phillips 3T MRI. FA was measured for 181 regions of the segmented brain using Eve atlas. 48 relevant regions with susceptibility for WMTD were analyzed. Serum ceramides were measured using high performance liquid chromatography. Spearman correlations and GEE linear regression analyses (adjusted for age, sex, race, education and family relatedness) were used. We set the significance level to meet the Bonferroni threshold of 0.00017 (0.05 / 48 regions/6 ceramides).Results: Subjects, N=112, had a mean age of 49± 11 years; education 14 ± 3 years; 49% male; 39% African American, 61% European American). Serum levels for ceramides designated C18:0, C20:0, and C22:0 were significantly negatively correlated with FA in the right fornix (C18:0, R=-0.40, p=1.3 x10-5, C20:0, R=-0.41, p= 6.1 x 10-6, C22:0, R=-0.33, p=4.3 x10-4). C18:0 was negatively correlated with the left genu of corpus callosum (R=-0.39, p=2.6 x10-5) and right body of corpus callosum (R=-0.31, p=8.5 x10-4). An additional ceramide, C24:0, was correlated with both sides of the posterior limb of internal capsule (left R=0.34, p=2.5 x10-4; right R=0.34, p=2.8 x10-4). All ceramide-FA associations were significant (p<0.05) after fully adjusted GEE regression.Conclusions: We show a robust relationship between serum ceramides and WMTD using FA in a middle-aged, cognitively intact at-risk population enriched for early WMH. Thus, serum ceramide levels may reflect subtle alterations in white matter tract microstructure at an early preclinical stage.