It cleaves more than a hundred type-I transmembrane substrates (Jurisch-Yaksi et al., 2013) including Notch (important for development and cancer), ErbB4 (involved in breast cancer), and the Amyloid Precursor Protein (APP), whose cleavage product is the toxic amyloid-β, a major hallmark in Alzheimer’s disease (Annaert and De Strooper, 2002; Selkoe and Hardy, 2016). The gene discussed is APP; the disease is early-onset autosomal dominant Alzheimer disease.