14). In the short term, these responses help the cell cope with the stress that led to the buildup of unfolded protein. However, when the insult persists and causes chronic ER stress, apoptosis can result, which could be associated with neuronal and synaptic loss in AD. It has been hypothesized that increased activation of the UPR plays a role in the development or progression of AD (reviewed by Gerakis and Hetz (52)). There are some reports suggesting that the PERK/eIF2α pathway of the UPR is activated in 5XFAD mice (15, –, 18), but other reports suggest that it is unchanged (19). The gene discussed is EIF2A; the disease is Alzheimer disease.