1 Physics Department, Concordia University, Montreal, Quebec H4B 1R6, Canada.
2 Centre EPIC and Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1N6, Canada.
3 School of Health, Concordia University, Montreal, Quebec H4B 1R6, Canada.
4 Department of Biomedical Science, Faculty of Medicine, Université de Montreal, Montreal, Quebec H3T 1J4, Canada.
5 Department of Radiology, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
6 Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
7 Alberta Children's Hospital Research Institute, University of Calgary, Calgary T3B 6A8, Canada.
8 McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec H4H 1R2, Canada.
9 Department of Biomedical Engineering, McGill University, Montreal, Quebec H3A 2B4, Canada.
10 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
11 Department of Medicine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
12 Research Center, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec H3W 1W6, Canada.

Coronary artery disease is associated with white matter alterations. However, the biological basis of these changes remains unclear, specifically in normal-appearing white matter. Myelin and iron content are crucial measures of white matter health and can be measured with quantitative MRI. This study investigated whether myelin and iron alterations occur in coronary artery disease, and their relationship with cognition. In this cross-sectional study, 46 individuals with coronary artery disease and 40 healthy controls aged > 50 years, with normal cognition underwent 3T MRI and cognitive assessments. Quantitative MRI metrics (susceptibility, magnetization transfer saturation (MTsat), R2* and R1 relaxation rates) were calculated in the border zones between adjacent arterial territories (watershed regions) and in the areas outside these borders (non-watershed regions) in normal-appearing white matter. Relative to controls, the coronary artery disease group showed lower myelin and higher iron content, as measured by lower MTsat and R1, and higher susceptibility specifically in watershed regions. Importantly, these microstructural alterations were associated with poorer cognitive performance in the coronary artery disease group with lower MTsat and R1 related to poorer global cognition and with higher magnetic susceptibility with poorer verbal memory. These findings suggest that coronary artery disease is associated with demyelination and iron deposition in normal-appearing white matter, most prominently in watershed regions, which are known for their susceptibility to stroke. The association of these microstructural alterations with cognition highlights the role of normal-appearing white matter as a key vulnerable region and a promising focus for future mechanistic and therapeutic studies.