White matter fractional anisotropy decreases precede hyperintensities in Alzheimer's disease

The associations of β-amyloid (Aβ) and tau deposition with white matter (WM) degeneration in Alzheimer's disease (AD) remain inadequately elucidated. We investigate baseline and longitudinal changes of microstructural fractional anisotropy (FA) and macrostructural white matter hyperintensities (WMHs) and their relationships with Aβ and tau positron emission tomography (PET) and vascular risk factors in different Aβ/tau stages defined by PET imaging. Lower levels and faster decline rates of FA occur in the AD continuum, particularly in tau-positive individuals. Tau-related FA decreases are correlated with higher burden and faster increase rates of WMH but not vice versa. These results are substantially replicated in an independent cohort. This study suggests that tau is tightly linked with microstructural WM degeneration, appearing earlier than macrostructural WM alteration in AD. Our findings provide valuable insights for detecting and monitoring early WM degeneration in AD, highlighting the importance of targeting tau clearance to maintain healthy WM integrity.