Cholinergic White Matter Lesions, AD-Signature Cortical Thickness, and Change in Cognition: The Northern Manhattan Study

BACKGROUND: How cerebrovascular disease and neurodegeneration affect each other to impact cognition is not yet known. We aimed to test whether Alzheimer's disease-signature (AD) cortical thickness mediates the association between cholinergic white matter lesion load and change in domain-specific cognition. METHODS: Clinically stroke-free participants from the Northern Manhattan Study with both regional white matter hyperintensity volume (WMHV) and gray matter measurements were included (N = 894). Tract-specific WMHVs were quantified through FSL using the Johns Hopkins University white matter tract atlas. We used Freesurfer 5.1 to estimate regional cortical thickness. We fit structural equation models, including multiple indicator latent change score models, to examine associations between white matter hyperintensity volume (WMHV) in cholinergic tracts, AD-signature region cortical thickness (CT), and domain-specific cognition. RESULTS: Our sample (N = 894) had a mean (SD) age = 70 (9) years, years of education = 10 (5), 63% women, and 67% Hispanics/Latinos. Greater cholinergic WMHV was significantly related to worse processing speed at baseline (standardized beta = -0.17, SE = 0.05, p = .001) and over time (standardized beta = -0.28, SE = 0.09, p = .003), with a significant indirect effect of AD-signature region CT (baseline: standardized beta = -0.02, SE = 0.01, p = .023; change: standardized beta = -0.03, SE = 0.02, p = .040). CONCLUSIONS: Cholinergic tract WMHV is associated with worse processing speed, both directly and indirectly through its effect on AD-signature region CT.