Elevated levels of FGF23 in individuals with chronic kidney disease (CKD) are associated with adverse health outcomes, such as increased mortality, large vessel disease, and reduced white matter volume, cardiovascular and cerebrovascular events. Apart from the well-known link between cardiovascular (CV) risk factors, especially diabetes and hypertension, and cerebrovascular damage, elevated FGF23 is also postulated to be associated with cerebrovascular damage independently of CKD. Elevated FGF23 predisposes to vascular calcification and is associated with vascular stiffness and endothelial dysfunction in the general population with normal renal function. These factors may lead to microangiopathic changes in the brain, cumulative ischemia, and eventually to the loss of white matter fibers. The relationship between FGF23 and brain integrity in individuals without CKD has hitherto not been investigated. In this study, we aimed to determine the association between FGF23, and white matter integrity in a cohort of 50 participants with varying degrees of CV risk burden, using high resolution structural human brain connectomes constructed from MRI diffusion images. We observed that increased FGF23 was associated with axonal loss in the frontal lobe, leading to a fragmentation of white matter network organization. This study provides the first description of the relationship between elevated levels of FGF23, white matter integrity, and brain health. We suggest a synergistic interaction of CV risk factors and FGF23 as a potentially novel determinant of brain health.