Converging lines of evidence from studies in cell culture (Rogaeva et al., 2007), knockout (KO) mouse models (Caglayan et al., 2014; Dodson et al., 2008), and individuals with AD indicate that loss of SORL1 function (i.e., haploinsufficiency) is a cause of monogenic AD, in addition to autosomal dominant missense mutations in APP, PSEN1, and PSEN2 (Sager et al., 2007; Scherzer et al., 2004). This evidence concerns the gene PSEN1 and Alzheimer disease.