Over the past decade, histological evidence of UPR activation, particularly the detection of phosphorylated PERK (PERK-P) and eIF2α-P, has increasingly been reported in post-mortem brain tissue from patients with Alzheimer’s disease, ALS, Parkinson’s disease, and also in the tauopathies progressive supranuclear palsy and frontotemporal dementia (Hoozemans et al., 2007, 2009; Atkin et al., 2008; Stutzbach et al., 2013). The gene discussed is EIF2AK3; the disease is early-onset autosomal dominant Alzheimer disease.