APP and Alzheimer disease: Alzheimer’s disease is a complex pathology that appears in early onset familial forms (~1–2% of all cases; hereditary disease linked to mutated genes encoding amyloid precursor protein APP, presenilins1 and 2, and tau protein) and late onset sporadic forms for which age is the main risk factor.580,581 Clinical progression of AD is defined first by massive synapse loss and subsequently by neuronal death, which ultimately results in profound brain atrophy and is clinically manifested by severe dementia.