Amyloid-Beta Immunotherapy for the Prevention and Treatment of Alzheimer Disease: Lessons from Mice, Monkeys, and Humans

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Abstract
Alzheimer disease (AD), the most common form of dementia, is without an effective cure or preventive treatment. Recently, amyloid-beta protein (Aβ) has become a major therapeutic target. Many efforts are underway to either reduce the production of Aβ or enhance its clearance. In 1999, Schenk and colleagues first showed that active immunization with full-length Aβ lowered cerebral Aβ levels in transgenic mice. These findings have been confirmed and extended in various transgenic mouse models of AD using both active and passive Aβ immunization. Cognitive improvement also has been reported in association with active and passive Aβ vaccination in AD-like mouse models, even in the absence of significant reductions in cerebral Aβ loads. In 2004, the authors reported that active immunization with fulllength Aβ in aged nonhuman primates, Caribbean vervets, reduced cerebral Aβ levels and gliosis. Proposed mechanisms of Aβ clearance by immunotherapy include disruption of Aβ aggregates, Aβ phagocytosis by microglia, neutralization of Aβ oligomers at the synapse, and increased efflux of Aβ from brain to blood. A phase IIa clinical trial was halted in 2002 because of the appearance of meningoencephalitis in ∼6% of the AD patients. Although the exact cause of these adverse events is unknown, the immunogen, full-length Aβ1-42, may have been recognized as a self-antigen leading to an autoimmune response in some patients. Limited cognitive stabilization and apparent plaque clearance have been reported in subsets of patients who generated antibody titers. Currently, a passive immunization trial with a recombinant humanized monoclonal Aβ antibody is underway in humans. In the meantime, the authors are developing novel Aβ peptide immunogens for active immunization to target Aβ B cell epitope(s) and avoid Aβ-specific T-cell reactions in order to generate a safe and effective AD vaccine. The authors remain optimistic about the potential of such a vaccine for the prevention and treatment of AD.