Background: White matter hyperintensities (WMH) are areas of increased signal observed on T2-weighted magnetic resonance imaging (MRI) that reflect macrostructural white matter damage frequently observed in aging. The extent to which diminished microstructure precedes or results from white matter damage is unknown. The aim of this study was to evaluate the hypothesis that white matter areas that show normatively lower microstructure are most susceptible to develop WMH.Methods: Five hundred fifty-seven older adults (age: 73.9±5.7yrs) underwent diffusion weighted imaging (DWI) and T2-weighted magnetic resonance imaging (MRI). Diffusion weighted imaging scans were processed into parametric maps of fractional anisotropy (FA) and T2weighted MRI scans were segmented into WMH. All images were spatially normalized to standard space. A FA template was created to represent normative values from a separate, independent sample of young, healthy adults (N=49, age: 25.8±2.8yrs) and a WMH frequency template was created from the segmented WMH in the older adults. We compared FA values between areas defined as WMH with those defined as normal appearing white matter (NAWM) in the older participants. White matter hyperintensity frequency was binned (0-5%, 5-10%, 10-15%, 15-20%, >20%) and we determined whether WMH frequency bins were different by normative FA values defined in the younger group.Results: Fractional anisotropy values were lower (p<0.001) in WMH regions compared with NAWM regions in the older sample. Areas with higher WMH frequency in older adults had lower FA values in younger adults (5-10%>10-15%>15-20%; p<0.001).3 Discussion: Low FA values are observed in frank WMH, but FA is also normatively low in regions with high WMH frequency prior to damage. Regions with normatively lower microstructure are more susceptible to future damage from factors such as chronic hypoperfusion or pathology. 4