APP and Alzheimer disease: According to this hypothesis, the increased production of self-aggregating forms of Aβ (e.g., Aβ42), due to missense mutations in the APP or other AD-related genes or failure in Aβ clearance, causes the gradual deposition of Aβ oligomers as diffuse plaques, microglial and astrocytic activation, oxidative injury, and formation of neurofibrillary tangles built of the hyperphosphorylated tau protein, together leading to widespread synaptic dysfunction and neuronal loss [152,153].