APP and Alzheimer disease: It is notable that just a 50% increase of Aβ production results in early Aβ deposition for some cases of FAD (APP gene duplication; Rovelet-Lecrux et al., 2006) and Down's syndrome (Selkoe and Hardy, 2016), implying that a 50% reduction of NEP expression/activity, which increases endogenous brain Aβ levels 1.5-fold (Iwata et al., 2001), is sufficient to cause pathological Aβ deposition leading to AD development.