PSEN1 and Alzheimer disease: Missense mutations in Presenilins account for a sizable fraction of familial AD cases and models of Presenilin-mediated neurodegeneration have been established in Drosophila. Recent analysis of 138 pathogenic mutations in PSEN1 demonstrate that approximately 90% compromise the function of the encoded γ-secretase (Sun et al. 2017) further supporting the hypothesis that neuronal loss is likely a consequence of this reduced function (Kelleher and Shen 2017).