Stage-Dependent mediation of white matter hyperintensities between plasma biomarkers and cognitive function in Alzheimer's disease.

White matter hyperintensities (WMHs) are common in Alzheimer's disease (AD) and may contribute to cognitive impairment. However, the associations between regional WMH volumes, cognitive domains, and plasma biomarkers remain unclear. This study aimed to explore these relationships across the AD spectrum. A total of 311 participants were enrolled, including healthy controls (HC), individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD. All participants underwent comprehensive neuropsychological assessment, brain magnetic resonance imaging, and plasma biomarker analysis. WMH volumes were segmented using United Imaging software and classified based on anatomical location: juxtaventricular WMH (juxWMH), periventricular WMH (pWMH), juxtacortical WMH (jcWMH), and deep WMH (dWMH). Correlations among regional WMH volumes, plasma biomarkers, and cognitive domains were analyzed with multiple comparisons. Path analysis was used to assess potential mediation effects. Mediation analyses using bootstrapping were conducted separately in cognitively unimpaired and cognitively impaired groups to assess WMH-mediated pathways between biomarkers and cognition. Compared with HC, SCD, and MCI groups, the AD group showed significantly increased log-transformed (lg) juxWMH volumes (all P < 0.05, Bonferroni corrected). The AD group showed significantly larger lgpWMH and lgjcWMH volumes than HC, SCD and AD groups (all P < 0.05). Lower plasma Aβ42/Aβ40 ratio was associated with higher lgjuxWMH, lgpWMH, and lgjcWMH volumes. Higher lgjuxWMH volume was associated with worse memory (r = -0.16, P = 0.006), language (r = -0.34, P < 0.001), and executive function (r = 0.18, P = 0.003). Similar trends were found for lgpWMH and lgjcWMH volumes. Mediation analysis revealed that in cognitively unimpaired individuals, juxWMH and pWMH primarily mediated amyloid-cognitive associations, while in cognitively impaired patients, mediation expanded to include neuroinflammatory and neurodegeneration pathways across multiple location-specific WMH. Location-specific WMH demonstrate stage-dependent mediation patterns in AD pathophysiology, evolving from amyloid-driven changes to multi-factorial processes. These findings provide insights for developing targeted therapeutic strategies at different disease stages.