The rationale for an immunological approach to Alzheimer's therapeutics

Abstract

Immunotherapy toward the Aβ peptide offers a unique therapeutic approach to the treatment of Alzheimer's disease. The rationale is that antibodies interacting with the Aβ peptide will accelerate its clearance from the CNS, lead to less amyloid deposition, and reduce the other pathological features of Alzheimer's disease. Evidence from transgenic mouse models of amyloid deposition is highly supportive of both pathological and functional benefits of this approach. Data from human trials of active immunization (using a vaccine to stimulate generation of antibodies) led to several apparent cases of autoimmune CNS inflammation. However, some of the patients with high titers of brain-reactive antibodies have remained cognitively stable for up to 3 years after the vaccinations were halted. This has led to the investigation of passive immunotherapy, where monoclonal antibodies are injected directly on a monthly or bimonthly schedule, as a possibly safer, yet still effective approach to immunotherapy. Passive immunotherapy is equally effective as vaccines in mouse models of amyloid deposition. Passive immunization also has the advantages of control over antibody dosage, antibody epitope, antibody isoptype, and the ability to withdraw the agent if adverse events do occur. Several clinical trials are presently underway investigating this immunotherapeutic approach.