PSEN1 and Alzheimer disease: While it has been made clear that the amyloid cascade hypothesis is not enough to sufficiently explain the development of AD or aid in its detection and consequently, is currently under heavy scrutiny, it is also not possible to accept the null hypothesis, as autosomal dominant mutations in the aforementioned APP, PSEN1 and PSEN2 genes along with the apolipoprotein E4 (APOE4) allele have been proven to be the key components in familial, or early onset, Alzheimer's disease.