APP and Alzheimer disease: Alternative, albeit less “physiological”, approaches, which bypass the iAβ accumulation stage, include the induction of mitochondrial dysfunction resulting in the HRI activation or stressor-specific activation of one of the other eIF2α kinases, all leading to the elicitation of the ISR and, provided that the ISR alone is sufficient to activate the AβPP-independent iAβ generation pathway and, consequently, the AD Engine, resulting in the commencement of the second AD stage.