As APP.C99 selectively accumulates in vulnerable neurons in AD [73] and is known to show increased presence at mitochondria-associated ER membranes [74], and β-cleavage activity is present at the ER [75–77] or the endosomes [78], our finding of RQC manipulation being effective in rescuing APP.C99-related toxicity in both APP.C99 and FL-APP contexts supports that inefficient QC of ER-associated stalled translation of APP is critically involved in the generation of toxic APP.C99 species during AD pathogenesis. The gene discussed is APP; the disease is Alzheimer disease.