The role of Aβ in AD pathogenesis was first proposed as part of the ‘amyloid cascade’ hypothesis following the observation that virtually all people with Down’s Syndrome (DS) will exhibit AD pathology by 40 years of age, and that there was concomitant overexpression of Aβ from the cloning of the APP gene with trisomy 21 (126). Here, APP is linked to Alzheimer disease.