Working hypothesis based on the amyloid cascade. The central event for the amyloid cascade hypothesis is the excessive formation of Aβ. The source of excessive Aβ formation is the amyloid precursor APP and multiple factors may contribute to its aberrant processing. Here we have indicated genetic alterations since it has been largely demonstrated that mutations associated with familial forms of Alzheimer's disease, result in aberrant metabolism and excess production of Aβ. Defective signal transduction mechanisms, neurotransmitter changes and other perturbations of normal cellular homeostasis may also contribute to aberrant APP processing. Most of these alterations have been detected and characterized in the brain and/or peripheral tissues of AD patients and constitute a significant example of the pharmacological modulability of the regulated processing of APP.