White matter microstructural metrics are sensitively associated with clinical staging in Alzheimer's disease

INTRODUCTION: White matter microstructure may be abnormal along the Alzheimer's disease (AD) continuum. METHODS: Diffusion magnetic resonance imaging (dMRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 627), Baltimore Longitudinal Study of Aging (BLSA, n = 684), and Vanderbilt Memory & Aging Project (VMAP, n = 296) cohorts were free‐water (FW) corrected and conventional, and FW‐corrected microstructural metrics were quantified within 48 white matter tracts. Microstructural values were subsequently harmonized using the Longitudinal ComBat technique and inputted as independent variables to predict diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI], AD). Models were adjusted for age, sex, race/ethnicity, education, apolipoprotein E (APOE) ε4 carrier status, and APOE ε2 carrier status. RESULTS: Conventional dMRI metrics were associated globally with diagnostic status; following FW correction, the FW metric itself exhibited global associations with diagnostic status, but intracellular metric associations were diminished. DISCUSSION: White matter microstructure is altered along the AD continuum. FW correction may provide further understanding of the white matter neurodegenerative process in AD. HIGHLIGHTS: Longitudinal ComBat successfully harmonized large‐scale diffusion magnetic resonance imaging (dMRI) metrics. Conventional dMRI metrics were globally sensitive to diagnostic status. Free‐water (FW) correction mitigated intracellular associations with diagnostic status. The FW metric itself was globally sensitive to diagnostic status. Multivariate conventional and FW‐corrected models may provide complementary information.