Fixel-based analysis reveals tau-related white matter changes in early stages of Alzheimer's disease

Several studies have shown white matter (WM) abnormalities in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aβ-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aβ-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics. Significance Statement Diffusion tensor imaging (DTI) has been widely used to study white matter (WM) integrity in Alzheimer's disease (AD). However, the methodological shortcomings of DTI limit an accurate biological interpretation. We used fixel-based analysis (FBA) to assess fiber-specific WM degeneration and its correlation with the underlying pathology and cognitive symptoms in early AD. Our results revealed that elevated tau- but not Aβ-PET uptake in the medial temporal structures was correlated with atrophy of the parahippocampal portion of the cingulum bundle. The tau-related damage in this WM bundle was further linked to memory deficits. Importantly, the tau-WM correlation was not detected by tensor-derived measures. These findings suggest that FBA metrics may serve as a biomarker for early detection of tau pathology in AD.