Amyloid and tau pathologies are drivers of white matter damage in aging and Alzheimers disease

BACKGROUNDWhite matter hyperintensities (WMHs) are increasingly recognized as markers of cerebrovascular pathology in Alzheimers 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 (A{beta}) and tau pathology and WMH burden in older adults. METHODSData from the Alzheimers Disease Neuroimaging Initiative (ADNI) included 1,241 older adults with A{beta} and 636 with tau for cross-sectional analyses. Longitudinal analyses included 670 participants for A{beta} change and 1,079 for WMH change (A{beta} group), and 199 for tau change and 356 for WMH change (tau cohort). Linear models were used to i) assess associations between baseline regional WMH and A{beta} and tau pathology, and ii) examine whether baseline pathology in one measure was associated with change in the other measure over two years. RESULTSBaseline analyses revealed significant bidirectional associations between WMH burden and both A{beta} (t=2.09-4.16, p<.05) and tau pathology (t=2.44-2.87, p<.04), with stronger effects in posterior brain regions. Longitudinal analyses showed that baseline A{beta} levels were associated with future WMH progression in frontal and occipital regions (t=2.44-3.27, p<.03), while baseline tau was linked to WMH increases in frontal and parietal regions (t=2.48-3.51, p<.03). However, baseline WMH burden was not associated with future accumulation of either A{beta} or tau pathology in any region. CONCLUSIONSThese findings suggest that A{beta} and tau pathology drive future WMH progression rather than the reverse, with distinct regional patterns for each pathology type.