Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by the
accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and
cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral
research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid
precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a singlepass
transmembrane protein expressed at high levels in the brain and metabolized in a rapid and
highly complex fashion by a series of sequential proteases, including the intramembranous γ-
secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in
the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ
elimination. Lessons learned from biochemical and genetic studies of APP processing will be
crucial to the development of therapeutic targets to treat AD.