APP and Alzheimer disease: Evidence that three copies of the APP gene are not only sufficient but also necessary to cause AD is provided by the fact that rare individuals who have full trisomy 21 and all of the clinical and physiological features of Down syndrome but have only two copies of the APP gene due to a localized deletion on chromosome 21 fail to develop AD symptoms or AD pathology even at an old age (Prasher et al., 1998; Doran et al., 2017).