1 Physics department, Concordia University, 7141 Rue Sherbrooke W, Montréal, QC H4B 1R6, Canada; Montreal Heart Institute, 5000 Rue Bélanger, Montréal, QC H1T 1C8, Canada; School of Health, Concordia University, 7200 Rue Sherbrooke W, Montréal, QC H4B 1R6, Canada. Electronic address: stefanie.tremblay@mail.concordia.ca.
2 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada; Department of Psychiatry, McGill University, 845 Rue Sherbrooke W, Montréal, QC H3A 0G4, Canada; McConnell Brain Imaging Centre, Montreal Neurological Institute, 845 Rue Sherbrooke W, Montréal, QC H3A 0G4, Canada; StoP-AD Centre, Douglas Mental Health Institute Research Centre, 6875 Blvd. LaSalle, Verdun, QC H4H 1R3, Canada.
3 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada.
4 School of Health, Concordia University, 7200 Rue Sherbr

Early detection of pathological changes in Alzheimer's disease (AD) has garnered significant attention in the last few decades as interventions aiming to prevent progression will likely be most effective when initiated early. White matter (WM) alterations are among the earliest changes in AD, yet limited work has comprehensively characterized the effects of AD risk factors on WM. In older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and risk factors. Multiple MRI-derived metrics were integrated using a multivariate approach based on the Mahalanobis distance (D2). To uncover the specific biological underpinnings of these WM alterations, we then extracted the contribution of each MRI feature to D2 in significant clusters. Lastly, the links between WM D2 and cognition were explored. WM D2 in several regions was associated with high systolic blood pressure, BMI, and glycated hemoglobin, and low cholesterol, in both males and females. APOE4 + displayed a distinct risk pattern, with LDL-cholesterol having a detrimental effect only in carriers, and this pattern was linked to immediate memory performance. Myelination was the main mechanism underlying WM alterations. Our findings reveal that combined exposure to multiple cardiometabolic risk factors negatively impacts microstructural health, which may subsequently affect cognition. Notably, APOE4 carriers exhibited a different risk pattern, especially in the role of LDL, suggesting distinct underlying mechanisms in this group.