James D. LeFevre, Yukti Vyas, Aditi Sathe, Niranjana Shashikumar, Kimberly R. Pechman, Yisu Yang, Alaina Durant, Praitayini Kanakaraj, Michael E. Kim, Chenyu Gao, Nancy R. Newlin, Karthik Ramadass, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Shannon L. Risacher, Panpan Zhang, Kurt G. Schilling, Annie Lee, Adam M. Brickman, Richard Mayeux, Jesse Mez, for the Alzheimer's Disease Neuroimaging Initiative (ADNI), Walter Kukull, Sarah Biber, Bennett A. Landman, Barbara B. Bendlin, Sterling C. Johnson, Julie Schneider, Lisa L. Barnes, David A. Bennett, Andrew J. Saykin, Michael L. Cuccaro, Timothy J. Hohman, Angela L. Jefferson, Derek B. Archer
INTRODUCTION: Vascular risk factors (VRFs) contribute to white matter microstructural degeneration, but their tract-specific contributions are unclear. We assessed the independent associations of four major VRFs with white matter microstructure in a large, multi-cohort study. METHODS: Diffusion magnetic resonance imaging data from five harmonized cohorts were free water (FW) corrected (n = 2961, 73.00 ± 9.27 years, 59.34% female). We associated body mass index (BMI) and presence of hypertension, diabetes, and heart disease with FW and FW-corrected diffusion metrics (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity) in 48 tracts. RESULTS: Hypertension and heart disease showed the most robust and widespread independent associations with white matter microstructure. In contrast, diabetes associations were attenuated in sensitivity analyses, while BMI associations were inconsistent across metrics. DISCUSSION: Hypertension and heart disease are associated most strongly with white matter microstructure, suggesting that tighter management of these conditions may more reliably yield benefits in preserving white matter health.