To test associations between the structural brain-based effects of Hcy and cognition separate from overall cardiovascular health, we adjusted mediation models for cardiorespiratory fitness measured by maximal oxygen uptake (VO2max) obtained during a treadmill graded exercise test (GXT), as well as other common AD and CVD risk factors (i.e., apolipoprotein E [APOE] ε4 status, hypertension status, smoking history, and additionally vitamin B12 levels). This evidence concerns the gene APOE and hypertensive disorder.