White matter injury, brain aging, and cognitive decline beyond amyloid/tau

BackgroundWhite matter injury in Alzheimer's disease is etiologically heterogeneous. Brain-predicted age difference (Brain-PAD) may capture structural vulnerability.ObjectiveTo test whether T1-weighted white matter signal abnormality burden (T1W-WMSA) is associated with Brain-PAD and whether Brain-PAD predicts cognitive decline and mild cognitive impairment (MCI)-to-Alzheimer's disease progression beyond white matter injury and amyloid/tau (A/T) status.MethodsHarmonized data from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC) were anchored to the cardiovascular-risk baseline. Cross-sectional regression tested associations between cardiovascular risk and T1W-WMSA and between T1W-WMSA and Brain-PAD. Mixed-effects and Cox models assessed cognitive decline and progression. We also evaluated sex interactions and A/T timing. Fluid-attenuated inversion recovery-derived white matter hyperintensity burden (FLAIR-WMH) was examined as a modality comparison.ResultsAmong 601 complete cases, cardiovascular-risk burden was not associated with T1W-WMSA (β = -0.0003, 95% confidence interval [CI] -0.0470 to 0.0463; p = 0.989), whereas T1W-WMSA was associated with higher Brain-PAD (β = 6.95 years per log-unit, 95% CI 5.71 to 8.19; p < 0.001). Among 369 participants, higher Brain-PAD predicted faster memory (β = -0.0244 per year; p < 0.001) and executive-function decline (β = -0.0153 per year; p < 0.001). Among 201 participants with MCI, Brain-PAD predicted progression to Alzheimer's disease (hazard ratio [HR] = 1.268, 95% CI 1.191 to 1.351; p < 0.001). The association persisted in the pre-outcome A/T-adjusted subset (HR = 1.333, 95% CI 1.203 to 1.477; p < 0.001). No prespecified sex interaction survived false-discovery-rate correction.ConclusionsWhite matter injury was associated with older-appearing brain structure but should not be interpreted as exclusively vascular. Brain-PAD provided prognostic information complementary to A/T staging and white matter lesion burden.