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

Abstract 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.