For example, network disruptions and increased spontaneous activity within cortical and hippocampal circuits have been reported in mouse models of AD overexpressing mutant human APP, as well as humans at early disease stages.19,64,65 While this has been attributed to the effects of increased downstream production of Aβ,66,67 other work, involving the overexpression of WT human APP and mutant human APP resistant to BACE cleavage, without an elevation in Aβ,68,69 have also reported a neuronal hyperactivity phenotype with APP gain of function. This evidence concerns the gene APP and Alzheimer disease.