The Development of Anti-Amyloid Therapy for Alzheimer’s DiseaseFrom Secretase Modulators to Polymerisation Inhibitors

The leading hypothesis of the pathophysiology of Alzheimer’s disease holds that the pivotal event is cleavage of the amyloid precursor protein to release intact the 42-amino-acid amyloid-β peptide (Aβ); this hypothesis best explains the known genetic causes of Alzheimer’s disease. If this theory is correct, optimal strategies for altering the disease process should be directed toward modifying the generation, clearance and/or toxicity of Aβ. Aβ is highly aggregable, spontaneously assuming a β-sheet conformation and polymerising into oligomers, protofibrils, fibrils and plaques. The relative contribution of the various forms of Aβ to neuronal dysfunction in Alzheimer’s disease remains uncertain; however, recent evidence implicates diffusible oligomeric species.