Independent Role of White Matter Hyperintensity Volume and Location in Alzheimer’s Disease Risk Beyond Hippocampal Atrophy

Abstract

Objective Increases in white matter hyperintensities (WMH) observed on brain MRI are associated with the onset of Alzheimer’s disease (AD) and cognitive decline. Recent hypotheses suggest that the impact of WMH on cognition may differ by their distance from the ventricular surface. This study aimed to investigate the effects of WMH volume and location, classified by distance from the ventricular surface, on cognitive function in individuals with AD.Methods A total of 112 normal cognition (NC) individuals and 171 patients with AD underwent clinical evaluation, volumetric MRI, and neuropsychological testing using the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease. WMH volume was categorized as juxtaventricular (JVWMH, <3 mm from ventricle), periventricular (PVWMH, 3–13 mm), and deep (DWMH, >13 mm).Results The mean WMH volume was significantly higher in AD group (20.7±18.2 mL) than in the NC group (6.8±8.1 mL, p<0.001). A tenfold increase in WMH volume led to a 5.967-fold increased risk of AD (95% confidence interval [CI]=1.550–22.986). A similar risk association was observed for PVWMH (OR=4.021, 95% CI=1.592–10.156), and DWMH showed a significant risk association (OR= 2.873, 95% CI=1.227–6.731). Total WMH, JVWMH, and PVWMH were associated with poorer performance in verbal fluency and memory tasks, while DWMH showed no significant cognitive association.Conclusion WMH volume and location independently contribute to AD risk and cognitive decline, with PVWMH and JVWMH particularly affecting executive and memory functions, regardless of hippocampal atrophy.