MAPT and Alzheimer disease: Nevertheless, in accordance with the hypothesis prompted by the vascular-driven theory of AD, cerebrovascular dysfunction and consequent hypoperfusion is suggested to be linked to (1) enhanced β-secretase protein expression, which potentiates Aβ overproduction and altered phosphorylated tau (Velliquette et al., 2005; Koike et al., 2010); (2) faulty clearance of Aβ peptides, favoring accumulation in the brain (Girouard and Iadecola, 2006) and (3) reduced supply of metabolic substrates and neurometabolic dysfunction.