Genetic deficiency of eNOS, in both in vitro studies of human brain microvascular ECs and in vivo studies in mice, causes increased endothelial expression of APP and β-secretase-1 (BACE-1), appearance of vascular and parenchymal Aβ, and cognitive deficits that are prevented by administration of l-arginine or a PDE5 inhibitor [70]. This evidence concerns the gene NOS3 and Cognitive impairment.