APP and Alzheimer disease: In the current transgenic animal models of AD, as reasoned above, AβPP-derived iAβ accumulates over the T1 threshold and the integrated stress response is elicited, but the AD pathology does not progress, judging by its major hallmark, the formation of neurofibrillary tangles, or rather by the lack thereof; indeed, there are no indications that the disease commences in the first place.