LAUSR

Targeting the amyloid‐β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β‐ and γ‐secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid‐degrading enzymes (ADEs) and by a variety of transport processes. The development of late‐onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin‐degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up‐regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research.