White matter hyperintensities and amyloid pathology in cognitively unimpaired aging: topographical, microstructural, and network-level evidence

The frequent coexistence of white matter hyperintensities (WMHs) and β-amyloid (Aβ) pathology in cognitively unimpaired older adults complicates interpretation of vascular and neurodegenerative imaging findings. This narrative review synthesizes topographical, microstructural, and network-level evidence in cognitively unimpaired aging, distinguishing biomarker-characterized samples from supportive mixed or symptomatic cohorts. WMHs have heterogeneous etiologies. Posterior and some periventricular patterns are associated with cerebral Aβ in several cohorts, but lobar location and distance from the ventricles are overlapping classifications, and vascular associations are not confined to frontal or deep lesions. Independent and additive cognitive associations are more consistently reported than interactions. Longitudinal executive-function interactions reported in a dissertation and related abstract remain preliminary and non-independent. Some longitudinal studies associate baseline Aβ with subsequent WMH accrual, but findings are not uniform and do not establish causation. APOE-related findings vary with age, population, and amyloid burden. Diffusion MRI detects tissue abnormalities beyond visible lesions, although microstructural and disconnectome measures require prospective validation before they can improve individual prognosis. Anti-amyloid trial evidence identifies MRI safety considerations; effects on chronic WMH progression remain uncertain.