Fibre density and cross-section associate with hallmark pathology in early Alzheimer's disease.

Background: Tau pathology in Alzheimer's disease (AD) propagates trans-synaptically along structurally connected brain networks and in synergy with amyloid pathology it induces synaptic damage. However, the in vivo relationship of amyloid, tau and synaptic density with white matter (WM) structural changes has been studied rather limitedly. Recent advances in diffusion MRI processing allow quantification of apparent fibre density and fibre cross-section on the fixel level, i.e., individual fibre populations within one voxel. The aim of this study was to investigate the hypothesis of axonal loss due to tau propagation and amyloid pathology and its association with synaptic density in early disease stages.

Methods: Twenty-four patients with amnestic mild cognitive impairment (aMCI) and 23 healthy controls (HC) underwent baseline amyloid (¹¹C-PiB/¹⁸F-NAV4694), tau (¹⁸F-MK-6240) and synaptic density (¹¹C-UCB-J binding to SV2A) PET/MR in combination with diffusion MRI and cognitive assessments. A subset of 14 aMCI patients underwent follow-up visits after 2 years. First, a whole-brain fixel-based analysis was performed to identify differences in fibre density and fibre cross-section between HC and aMCI and longitudinally in the aMCI group. Next, a tract-of-interest analysis was performed, focusing on the temporal-cingulum bundle where most alterations have been shown in early AD. Tau and SV2A PET were quantified in the connected regions, i.e., hippocampus and posterior cingulate/precuneus (PCC-P). Amyloid PET centiloids were measured in the commonly used cortical composite volume-of-interest.

Results: At baseline, multiple WM tracts showed lower fibre density and lower fibre cross-section in aMCI compared to HC, and these parameters further decreased longitudinally in the aMCI group. In the temporal cingulum bundle, reduced fibre density was significantly associated with reduced hippocampal synaptic density while increased hippocampal and PCC-P tau specifically correlated with reduced fibre cross-section. Increased global amyloid burden was associated with reduced fibre density and fibre cross-section in the temporal cingulum bundle.

Conclusions: Our results suggest that WM degeneration already occurs in the aMCI stage of AD and alterations in apparent fibre density and fibre cross-section of the temporal cingulum bundle are associated with AD hallmark pathology.