Peak width of skeletonized mean diffusivity reveals early and multifactorial white matter injury across sporadic and Down syndrome-associated Alzheimer's disease.

INTRODUCTION: This study investigates the evolution with disease progression and pathological correlates of peak width of skeletonized mean diffusivity (PSMD), a sensitive diffusion magnetic resonance imaging (MRI) marker of microvascular white matter (WM) injury, in sporadic Alzheimer's disease (sAD) and Down syndrome (DS)-associated AD (DSAD). METHOD: This cross-sectional study included 150 euploid controls, 118 subjects with sAD, and 228 DS adults (34.65% with symptomatic AD). PSMD was derived from 3T-MRI diffusion tensor imaging. Associations with sociodemographic, clinical stage, cerebrospinal fluid (CSF), and small vessel disease markers were examined. RESULTS: PSMD correlated with age in all groups, showing a stronger association in DS, with alterations apparent 15 years before the population's dementia age at onset. In euploid and DS, higher PSMD correlated with AD severity, CSF-neurofilament light chain (NfL), microbleeds, and WM hyperintensities (WMH). PSMD abnormalities were more frequent than WMH, especially in DS. DISCUSSION: PSMD is a sensitive early biomarker of WM injury across sAD and DSAD, preceding symptom onset and capturing multifactorial disease processes.