Cognitive decline and the progression to Alzheimer's disease (AD) are traditionally associated with amyloid-beta (Aβ) and tau pathologies. This study aims to evaluate the relationships between microstructural white matter injury, cognitive decline and AD core biomarkers.

We conducted a longitudinal study of 566 participants using peak width of skeletonized mean diffusivity (PSMD) to quantify microstructural white matter injury. The associations of PSMD with changes in cognitive functions, AD pathologies (Aβ, tau, and neurodegeneration), and volumes of AD-signature regions of interest (ROI) or hippocampus were estimated. The associations between PSMD and the incidences of clinical progression were also tested. Covariates included age, sex, education, apolipoprotein E4 status, smoking, and hypertension.

Higher PSMD was associated with greater cognitive decline (β=-0.012, P < 0.001 for Mini-Mental State Examination score; β<0, P < 0.05 for four cognitive domains) and a higher risk of clinical progression from normal cognition to mild cognitive impairment (MCI) or AD (Hazard ratio=2.11 [1.38–3.23], P < 0.001). These associations persisted independently of amyloid status. PSMD did not predict changes in Aβ or tau levels, but predicted changes in volumes of AD-signature ROI (β=-0.003, P < 0.001) or hippocampus (β=-0.002, P = 0.010). Besides, the whole-brain PSMD could predict cognitive decline better than regional PSMDs.

PSMD may be a valuable biomarker for predicting cognitive decline and clinical progression to MCI and AD, providing insights besides traditional Aβ and tau pathways. Further research could elucidate its role in clinical assessments and therapeutic strategies.