Global and regional white matter hyperintensities in Alzheimer's disease: Exploring etiologies and cognitive correlates

Background White matter hyperintensities (WMH) are commonly observed in Alzheimer's disease (AD), but their underlying pathophysiology remains poorly understood. Objective This cross-sectional study aims to explore the multifactorial etiologies and cognitive correlates of global and regional WMH in a cohort of biologically diagnosed AD patients. Methods We included 170 AD patients who underwent brain MRI, neuropsychological testing, and cerebrospinal fluid (CSF) biomarker evaluation within three months. Linear and logostic regressions were used to assess associations between global/regional WMH and age, cerebral microbleeds (CMB), AD biomarkers, cortical atrophy, and vascular risk scores. Sensitivity analyses included replacing vascular score with hypertension, p-tau181 with t-tau, and inclusion of APOE ε4 status. Associations between Mini-Mental State Exam scores and WMH and atrophy burden were also evaluated, adjusting for age, sex, and education. Results Greater global WMH burden was significantly associated with older age (β = 0.03, p < 0.001), lower CSF Aβ 42 levels (β = −0.0014, p = 0.01), and more severe CMB grade (β = 0.48, p = 0.003), but not with vascular risk scores. Regionally, WMH in the paraventricular, frontal, and parietal lobes were linked to CSF Aβ 42 and CMB. Cognitive impairment was independently associated with increased paraventricular WMH burden (β = −0.22, p < 0.001) and medial temporal atrophy (β = −0.82, p < 0.001). Conclusions Our findings suggest that WMH in AD—particularly in the paraventricular, frontal, and parietal areas—are driven more by AD-specific pathology, including amyloid deposition and cerebral amyloid angiopathy, than by conventional vascular risk. Paraventricular WMH contribute to cognitive decline independent of cortical atrophy, underscoring their relevance as potential imaging biomarkers in AD.