White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

White matter lesions are highly prevalent in individuals with Alzheimer's disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T-1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer's Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age-and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.