White Matter Degeneration Pathways Associated With Tau Deposition in Alzheimer Disease

The dynamics of white matter (WM) changes are understudied in Alzheimer disease (AD). Our goal was to study the association between flortaucipir PET and WM health using neurite orientation dispersion and density imaging (NODDI) and evaluate its association with cognitive performance. Specifically, we focused on NODDI's Neurite Density Index (NDI), which aids in capturing axonal degeneration in WM and has greater specificity than single-shell diffusion MRI methods. We estimated regional flortaucipir PET standard uptake value ratios (SUVRs) from 3 regions corresponding to Braak stage I, III/IV, and V/VI to capture the spatial distribution pattern of the 3R/4R tau in AD. Then, we evaluated the associations between these measurements and NDIs in 29 candidate WM tracts using Pearson correlation and multiple regression models. Based on 223 participants who were amyloid positive (mean age of 78 years and 57.0% male, 119 cognitively unimpaired, 56 mild cognitive impairment, and 48 dementia), the results showed that WM tracts NDI decreased with increasing regional Braak tau SUVRs. Of all the significant WM tracts, the uncinate fasciculus ( = -0.274 for Braak I, -0.311 for Braak III/IV, and -0.292 for Braak V/VI, < 0.05) and cingulum adjoining hippocampus ( = -0.274, -0.288, -0.233, < 0.05), both tracts anatomically connected to areas of early tau deposition, were consistently found to be within the top 5 distinguishing WM tracts associated with flortaucipir SUVRs. The increase in tau deposition measurable outside the medial temporal lobes in Braak III-VI was associated with a decrease in NDI in the middle and inferior temporal WM tracts. For cognitive performance, WM NDI had similar coefficients of determination ( = 31%) as regional Braak flortaucipir SUVRs (29%), and together WM NDI and regional Braak flortaucipir SUVRs explained 46% of the variance in cognitive performance. We found spatially dependent WM degeneration associated with regional flortaucipir SUVRs in Braak stages, suggesting a spatial pattern in WM damage. NDI, a specific marker of axonal density, provides complementary information about disease staging and progression in addition to tau deposition. Measurements of WM changes are important for the mechanistic understanding of multifactorial pathways through which AD causes cognitive dysfunction.