APP and Alzheimer disease: In this regard, we note that the inhibition of γ-secretase in the adult mouse brain leads to age-dependent neurodegenerative phenotypes (Acx et al., 2017; Wines-Samuelson et al., 2010; Tabuchi et al., 2009; Saura et al., 2004) by poorly understood but APP-independent mechanisms (Acx et al., 2017), whereas pharmacological inhibition of γ-secretase has been linked to cognitive worsening in AD affected individuals (Doody et al., 2013).