In many but not all APP models, the onset of cognitive decline occurs in close proximity to that of amyloid deposition, such as in the CRND8 model [51], but has been identified both months prior to pathology in the Tg2576 model [52, 53] and months afterwards in the 5XFAD [47] and tet-off APP models (Chiang et al., in press). This evidence concerns the gene APP and Mental deterioration.