Bundle-specific associations between white matter microstructure and Aβ and tau pathology at their connecting cortical endpoints in older adults at risk of Alzheimer’s disease

Abstract

Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer’s disease (AD), are believed to spread through connected regions. Combining diffusion imaging and positron emission tomography, we investigated associations between Aβ, tau and white matter microstructure specifically in bundles connecting brain regions in which AD pathology accumulates. In 126 cognitively normal elderly at risk of AD, we focussed on free-water corrected diffusion measures in the cingulum, posterior cingulum, fornix and uncinate fasciculus. We found higher tissue fractional anisotropy and lower mean and radial diffusivity related to increased Aβ at the cortical endpoints of the cingulum and fornix. We observed similar but stronger associations in the uncinate fasciculus, but with increased Aβ and tau at the endpoints of this bundle. This consistent pattern of associations, with opposite directionality to the usual degeneration pattern in symptomatic individuals, suggests more restricted diffusion in bundles vulnerable to preclinical AD pathology.

Fixel-based analysis reveals macrostructural white matter changes associated with tau pathology in early stages of Alzheimer’s disease

“…However, further adjustments for the GM volume of the MTL regions decreased the effect size suggesting that the tau-FC association is not entirely independent from GM atrophy. Consistent with our findings, prior works have identified an association between increased tau-PET uptake and WM alterations in temporoparietal pathways (Binette et al, 2021;Luo et al, 2021;Jacobs et al, 2018;Strain et al, 2018).…”

“…The lack of an association between amyloid accumulation and WM degeneration, as suggested by our results, is in agreement with previous reports using both DTI (Strain et al, 2018) and FBA (Mito et al, 2018). In contrast, other studies have shown either a negative or a positive correlation between FBA-or tensor-derived metrics with global Aβ-PET uptake in different stages of AD (Dewenter et al, 2022;Luo et al, 2021;Binette et al, 2021;Benitez et al, 2022). Although the observed discrepancy might arise from differences in the selection of participants or analytical approach, our results suggest that tau aggregation is more closely linked to WM alterations than Aβ pathology.…”