Associations of Alzheimer's Disease Pathology and Small Vessel Disease With Cerebral White Matter Degeneration: A Tract‐Based MR Diffusion Imaging Study

White matter (WM) degeneration is a key feature of Alzheimer's disease (AD). However, the underlying mechanism remains unclear.To investigate how amyloid-β (Aβ), tau, and small vascular disease (SVD) jointly affect WM degeneration in subjects along AD continuum.Retrospective.152 non-demented participants (age: 55.8-91.6, male/female: 66/86) from the ADNI database were included, classified into three groups using the A (Aβ)/T (tau)/N pathological scheme (Group 1: A-T-; Group 2: A+T-; Group 3: A+T+) based on positron emission tomography data.3T; T1-weighted images, T2-weighted fluid-attenuated inversion recovery images, T2*-weighted images, diffusion-weighted spin-echo echo-planar imaging sequence (54 diffusion directions).Free-water diffusion model (generated parameters: free water, FW; tissue fractional anisotropy, FAt; tissue mean diffusivity, MDt); SVD total score; Neuropsychological tests.Linear regression analysis was performed to investigate the independent contribution of AD (Aβ and tau) and SVD pathologies to diffusion parameters in each fiber tract, first in the entire population and then in each subgroup. We also investigated associations between diffusion parameters and cognitive functions. The level of statistical significance was set at p < 0.05 (false discovery rate corrected).In the entire population, we found that: 1) Increased FW was significantly associated with SVD and tau, while FAt and MDt were significantly associated with Aβ and tau; 2) The spatial pattern of fiber tracts related to a certain pathological marker is consistent with the known distribution of that pathology; 3) Subgroup analysis showed that Group 2 and 3 had more alterations of FAt and MDt associated with Aβ and tau; 4) Diffusion imaging indices showed significant associations with cognitive score in all domains except memory.WM microstructural injury was associated with both AD and SVD pathologies, showing compartment-specific, tract-specific, and stage-specific WM patterns.1 TECHNICAL EFFICACY: Stage 3.