Based on the critical phenotype previously observed in APPYG/YG mice, which resulted in premature aging and cognitive and learning deficits (Matrone et al., 2011, 2012), and the potential role of SorLA as a predictive factor of neurodegeneration in AD patients (Rogaeva et al., 2007; Alexopoulos et al., 2011; Caglayan et al., 2014), we believe that these results strongly underscore the relevance of the correct APP binding to adaptor proteins, via Y682ENPTY687 domain, as a future potential strategy to prevent neurodegeneration in vivo. This evidence concerns the gene APP and Alzheimer disease.