Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of β-amyloid (Aβ), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Aβ is generated by proteolytic processing of the β-amyloid precursor protein (APP). Most individuals with Down syndrome (DS) have three copies of APP, leading to elevated APP expression, increased Aβ deposition, and characteristic AD neuropathology. Sequencing of APP in familial early-onset AD identified missense mutations that cause AD, while a recently discovered coding variant, APP A673T, reduces the risk for AD. Cellular and animal studies show that risk-associated mutations increase total Aβ levels, Aβ42 levels, or Aβ fibrillogenesis, while protective alleles reduce Aβ levels. Together, these studies provide compelling evidence for the Aβ hypothesis and suggest that therapeutics that reduces Aβ levels or Aβ fibrillogenesis should lower the risk for or prevent AD.