Introduction: Decreased fornix fractional anisotropy (FA) on diffusion tensor imaging (DTI) in normal ageing has been associated with impaired problem solving, working memory and motor tasking, but its role in multi-dimensional cognitive-motor tasks in apparently healthy people has not been studied. Also, the extent of its association with vascular disruption remains unclear. White matter lesions of presumed ischemic origin on MRI are associated with decrements in Grooved Pegboard test (GPBT) in young asymptomatic family members of probands with premature coronary artery disease (CAD). Hypothesis: We hypothesized that decrements in GPBT in this population, is associated with decreased FA in relevant brain regions. Methods: The GPBT was averaged for both hands. DTI was acquired on a Phillips 3T scanner (slice thickness 2.2 mm, field of view 212X212 mm and b-value 700 mm 2 /s). The brain was segmented into 181 regions with Large Deformation Diffeomorphic Metric Mapping using the Eve atlas. Pearson correlations of regional FA values and log-transformed GPBT scores were performed and Multivariable GEE linear regression (adjusted for family relatedness) was done for regions meeting the Bonferroni threshold of 0.00028 (0.05/181). Results: Subjects with DTI and GPBT data were included (N=115, mean age 49± 11 years; mean education 14 ± 3 years; 49% male; 41% African American). GPBT score was normal (106±15) seconds. Higher GPBT (worse performance) was negatively correlated with FA in regions of the left (L) and right (R) frontal and temporal lobes and L&R corpus callosum not meeting Bonferroni threshold (p=0.0046, 0.036, 0.026, 0.0015, 0.02, 0.0007), whereas the L&R fornix and L external capsule (EC) did meet threshold (L fornix R=-0.37, p=5.9E-05; R fornix R=-0.47, p=1.3E-07, L EC R=-0.35, p=8.1E-05). After adjusting for age, sex, race, and education every 25% lower FA in the R fornix was associated with 12% decrement in GBPT (R fornix p=0.05, L fornix and EC p=0.19). Conclusions: Decreased fornix FA is associated with worse manual dexterity in a healthy middle-aged population with a family history of early onset CAD, at risk for future cerebrovascular disease. This suggests injury of the fornix fibers may represent early ischemic injury in this population.