White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults

INTRODUCTION White matter hyperintensities (WMH), a key imaging biomarker of small vessel injury, may play a complex role in Alzheimer's disease (AD). We hypothesize that WMH not only directly contributes to cognitive decline but also moderates the relationship among AD pathology, treatment, and cognitive decline. METHODS A total of 1169 participants with 240‐week follow‐up in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were analyzed. Linear regression models examined WMH's contribution to cognitive decline, its interaction with Aβ on p‐Tau217 level, and its interaction with anti‐amyloid treatment on cognitive decline. RESULTS Increase in WMH volume independently contributed to cognitive decline ( p = 0.0028). Baseline WMH significantly moderated the relationship between Aβ change and p ‐Tau217 change ( p = 0.0035). Specifically, Aβ accumulation correlated with p‐Tau217 increase only in participants with low baseline WMH. WMH growth was associated with cognitive decline only in the treatment group ( p < 0.0001). DISCUSSION WMH modulates the interplay of pathologies, emphasizing the need for comprehensive treatment approaches targeting multiple pathways. Highlights White matter hyperintensity (WMH) independently contributed to cognitive decline. WMH modulated the longitudinal relationship between Aβ and p‐Tau217. WMH interacted with anti‐amyloid treatment on longitudinal cognitive decline.