The role of animal models in advancing amyloid-beta immunotherapy to the clinic

The available treatment options for Alzheimer's disease (AD), the most common chronic, progressive (and inevitably fatal) dementing neurological disease, have been disappointing in both their paucity and effectiveness as compared to other areas of medical intervention such as cardiovascular disease and oncology. The AD therapeutic picture is hopefully on the verge of a major positive change, as numerous clinical trials are now testing agents specifically designed to target hypothesized etiologic agents of AD, as opposed to the current class of approved therapies that offer only modest and transient symptomatic relief. One such hypothesis-driven approach is amyloid-beta (Aβ) immunotherapy, which is under investigation in over a dozen clinical trials by a multitude of different sponsors, including several late stage phase 3 studies. The results of these trials are eagerly anticipated as the underlying rationale directly tests the Aβ hypo thesis and is supported by extraordinarily compelling preclinical data. Both the scientific origin and evolution of this approach were intimately interwoven with the successful exploitation of human genetic findings that led to the development of transgenic animal models of this progressive central nervous system disease.Over a century ago, Dr Alois Alzheimer described the neuropathological brain lesions that, to this day, are essential in the post-mortem confirmation of AD diagnosis, namely amyloid plaques and neurofibrillary tangles. These lesions are composed primarily of the Aβ peptide and microtubule-associated tau protein, respectively, leaving the field to question whether one, both or neither of these proteins are causative of AD. Aβ is a peptide prone to self-aggregation and fibril formation leading to formation of extracellular plaques. The identification of genetic mutations - linked to autosomal dominant forms of AD in the amyloid precursor protein, from which Aβ is derived - not only bolstered the amyloid hypothesis but a