Thus, it could be argued that if the endogenous mouse AβPP gene is modified so that its transcripts contain sufficiently complementary TCE and ICE elements lacking the 3′ overhang, the elicitation of the ISR via overexpression of exogenous Aβ or by other means (discussed above) would activate RNA-dependent amplification of the endogenous AβPP mRNA and consequently the AβPP-independent iAβ production pathway, and that this, in turn, would trigger the commencement and progression of AD. Here, APP is linked to Alzheimer disease.