Amyloid and tau pathologies are drivers of white matter damage in aging and Alzheimer's disease.

White matter hyperintensities (WMHs) are increasingly recognized as neuroimaging biomarkers of cerebrovascular pathology in Alzheimer's disease (AD), yet their temporal relationship with amyloid and tau accumulation remains unclear. While previous studies suggest bidirectional associations between WMHs and AD pathology, regional associations between WMHs and AD pathology have yet to be examined. This study investigated the temporal and regional associations between PET measures of amyloid (Aβ) and tau pathology and WMH burden in older adults. Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) included 1,241 older adults with Aβ and 636 with tau for cross-sectional analyses. Longitudinal analyses included 613 participants for Aβ change and 980 for WMH change (Aβ group), and 92 for tau change and 342 for WMH change (tau group). Linear models were used to i) assess associations between baseline regional WMH and Aβ and tau pathology, and ii) examine whether baseline pathology in one measure was associated with change in the other measure over two years. Baseline analyses revealed significant bidirectional associations between WMH burden and both Aβ (t = 2.29-3.70, p < .05) and tau pathology (t = 2.01-2.56, p < .05). Longitudinal analyses showed that baseline Aβ levels were associated with future WMH progression in frontal and parietal regions and in anterior and posterior composite regions (t = 2.07-3.09, p < .04), while baseline tau was linked to WMH increases in parietal regions (t = 2.98, p < .03). However, baseline WMH burden was not associated with accumulation of Aβ or tau pathology in any region. These findings suggest that Aβ and tau pathology drive future WMH progression rather than the reverse, with distinct regional patterns for each pathology type.