APP and Alzheimer disease: Cerebrovascular dysfunction can lead to disrupted oxygen metabolism through hypoperfusion-hypoxia and hypoxia in-turn can enhance AD pathology by promoting tau phosphorylation as well as transcriptionally upregulating the HIF-1 target, β-site β-amyloid precursor protein cleavage enzyme 1 (BACE1) that cleaves amyloid precursor protein (APP) to produce Aβ (Figure 3; Sun et al., 2006).