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.