Active immunotherapy options for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common cause of dementia and a major contributor to disability and dependency among older people. AD pathogenesis is associated with the accumulation of amyloid-beta protein (Aβ) and/or hyperphosphorylated tau protein in the brain. At present, current therapies provide temporary symptomatic benefit, but do not treat the underlying disease. Recent research has thus focused on investigating the molecular and cellular pathways and processes involved in AD pathogenesis to support the development of effective disease-modifying agents. In accordance with the existing Aβ-cascade hypothesis for AD pathogenesis, immunotherapy has been the most extensively studied approach in Aβ-targeted therapy. Both passive and active immunotherapies have been shown to effectively reduce Aβ accumulation and prevent downstream pathology in preclinical models. Following AN1792, second-generation active immunotherapies have shown promising results in terms of antibody response and safety. Comparatively, tau immunotherapy is not as advanced, but preclinical data support its development into clinical trials. Results from active amyloid-based immunotherapy studies in preclinical models indicate that intervention appears to be more effective in early stages of amyloid accumulation, highlighting the importance of diagnosing AD as early as possible and undertaking clinical trials at this stage. This strategy, combined with improving our understanding of the complex AD pathogenesis, is imperative to the successful development of these disease-modifying agents. This paper will review the active immunotherapies currently in development, including the benefits and challenges associated with this approach.

Figure 1

Immunotherapy approach to beta-amyloid clearance. Aβ, amyloid-beta protein; BBB, blood–brain barrier; CNS, central nervous system; mAb, monoclonal antibody.

Figure 2

Amyloid deposition in the neocortex of APP24 mice after treatment with CAD106 and vehicle. (A) Treatment with vehicle. (B) Treatment with CAD106. Reprinted from [10]. © 2011, with permission from Society for Neuroscience.

Figure 3

Mean amyloid-beta protein-specific antibody response with CAD106, by IgM and IgG titers. (A) IgM titers. (B) IgG titers. Aβ, amyloid-beta protein. Reprinted from [21]. © 2012, with permission from Elsevier.