1 Physics Department, Concordia University, 7141 Rue Sherbrooke W, Montréal, QC, H4B 1R6, Canada.
2 Centre Epic and Research Center, Montreal Heart Institute, 5000 Rue Bélanger, Montréal, QC, H1T 1C8, Canada.
3 School of Health, Concordia University, 7200 Rue Sherbrooke W, Montréal, QC, H4B 1R6, Canada.
4 Department of Biomedical Science, Faculty of Medicine, Université de Montreal, 2900 Edouard Montpetit Blvd, Montreal, QC, H3T 1J4, Canada.
5 BrainLab, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, 2075 Bayview Ave, North York, Toronto, ON, M4N 3M5, Canada.
6 Dr Sandra Black Centre for Brain Resilience and Recovery, Sunnybrook Research Institute, 2075 Bayview Ave, North York, Toronto, ON, M4N 3M5, Canada.
7 Department of Psychology, Concordia University, 7141 Rue Sherbrooke W, Montréal, QC, H4B 1R6, Canada.
8 McConnell Brain Imaging Centre, Montreal Neurological Institute, 3801 Rue University, Montreal, QC, H3A 2B4, Canada.
9 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 Rue University, Montreal, QC, H3A 2B4, Canada.
10 Department of Biomedical Engineering, McGill University, 845 Rue Sherbrooke W, Montréal, QC, H3A 0G4, Canada.
11 Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstraße 1a, 04103 Leipzig, Germany.
12 Department of Medicine, Université de Montreal, 2900 Edouard Montpetit Blvd, Montreal, QC, H3T 1J4, Canada.
13 Research Center, Institut Universitaire de Gériatrie de Montréal, 4545 Queen Mary Road Montreal, QC, H3W 1W4, Canada.

Patients with coronary artery disease (CAD) face an increased risk of cognitive impairment, dementia, and stroke. While white matter (WM) lesions are frequently reported in patients with CAD, the effects on WM microstructure alterations remain largely unknown. We aimed to identify WM microstructural alterations in individuals with CAD compared to healthy controls (HC), and to examine their relationships with cognitive performance. Forty-three (43) patients with CAD (35 males and 8 females) and 36 HC (26 males and 10 females) aged 50 and older underwent comprehensive neuropsychological testing and multi-modal 3T magnetic resonance imaging (MRI). A novel multivariate approach - the Mahalanobis distance (D2) - was used to quantify WM abnormalities as the amount of deviation from the HC reference group. D2 integrates multiple MRI-derived diffusion-weighted imaging, R1 relaxometry, and magnetization transfer imaging metrics, while accounting for covariance between metrics. Relationships between WM D2 and cognition (executive function and processing speed) were also assessed. Compared to HCs, patients with CAD had higher D2 values in the whole WM (p = 0.015) and in the right anterior, and bilateral middle cerebral artery territories (p<0.05). Myelin-sensitive metrics, particularly R1 relaxation rate and MT saturation, were the most important contributors to D2. Processing speed was positively associated with greater R1 in both the whole WM and left middle cerebral artery territory. These findings suggest that greater WM microstructural alterations observed in patients with CAD were mainly driven by differences in myelin content. These alterations may contribute to a heightened risk of cognitive impairment. Significance statement Coronary artery disease (CAD) is linked to a higher risk of cognitive decline, yet the underlying brain changes remain poorly understood. This study used advanced brain imaging and a novel multivariate method to detect subtle white matter alterations in individuals with CAD compared to healthy adults. The findings reveal widespread microstructural differences in brain white matter, particularly related to myelin-a substance critical for efficient brain communication. These changes were also related to slower processing speed, a key marker of cognitive aging. These findings provide new insight into how CAD may affect brain health and cognition, and could inform future efforts to detect and prevent cognitive decline in this population.