White matter microstructure disruption associated with PET and cognitive impairment in Alzheimer’s disease

Alzheimer’s disease (AD) is associated with regional brain atrophy as well as elevated positron emission tomography (PET) markers of amyloid-beta (e.g., ¹⁸Fflorbetapir (FBP)) and tau protein (e.g., ¹⁸Fflortaucipir (FTP). White matter microstructures have also been shown to be disrupted in AD, but there is limited understanding of their specific associations with FBP, FTP, and cognitive impairment. Herein, we used both voxel-based and fixel-based analyses of diffusion tensor imaging (DTI) to characterize microstructural white matter changes associated with PET and cognitive changes in AD. A retrospective study was performed using the data from 381 ADNI-3 participants (F:M = 200:181). FBP and FTP results were correlated with DTI metrics, including the apparent fiber density (AFD), complexity (CX), functional anisotropy (FA), fixel number (FN), and mean diffusivity (MD). Linear regression analysis was performed, adjusted for age, sex, education, and cognitive impairment. Greatest negative correlations were observed between FN and FBP standardized uptake value ratio (SUVR) in 15 out of 18 white matter tracts examined (beta coefficients of −0.3991 to −0.2877). No significant correlation was observed between DTI measures and FTP SUVR, independently. However, combined PET positivity (FBP + /FTP+) generally showed the greatest reductions in CX, FN, and FA of various tracts, compared to single PET-positive or PET-negative groups. Widespread changes in FA were positively associated with cognitive impairment, with stronger associations seen with the Montreal Cognitive Assessment (MoCA) than the Mini-Mental State Examination (MMSE). Only females showed significant correlations between MD and FBP/FTP levels and showed more widespread correlations between FA and MD changes and cognitive impairment. Taken together, these findings suggest specific patterns of white matter microstructure disruption in AD with underlying sex differences and support their potential role as early biomarkers.