Support for AD pathology relating to plaque formation was initially advanced by the identification of mutations in patient populations with an early onset (familial) form of AD [25], arising from a range of loss-of-function mutations in components of the γ-secretase complex, especially in two presenilin proteins (Psen1 and Psen2), and in the amyloid precursor protein (APP) that is cleaved by the γ-secretase complex to form amyloid-β proteins. Here, APP is linked to Alzheimer disease.