Immunotherapy for Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which memory and cognitive dysfunctions are the earliest symptoms. Pathologically, the disorder is characterized by neuron loss in hippocampus and multiple cortical regions, along with the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. The amyloid in this disorder is comprised largely of a peptide called Aß, which is a degradation product of a protein with unknown function referred to as the amyloid precursor protein. The genetics of dominant inherited forms of Alzheimer’s disease implicate increased production of the long form of the Aß peptide as the critical feature leading to unavoidable development of the disease. This recognition has led many to consider anti-amyloid therapeutics as a means of slowing or arresting the disease. One approach that may become the first to test the so-called “amyloid hypothesis“ is immunotherapy. Both vaccination and monoclonal antibody therapies have been tested with considerable success in mouse models of amyloid deposition. These approaches can prevent the formation of amyloid deposits, remove already existing deposits, and reverse the memory deficits associated with amyloid deposition in these mice. A human clinical trial was cut short due to an apparent autoimmune reaction in a fraction of the patients, but the results from this truncated trial still suggest that there may be therapeutic benefits of the approach. Current research is focusing on trying to understand the mechanisms by which antibodies directed against Aß aid in clearing the amyloid deposits, how the vaccines might be constructed to overcome self-tolerance without evoking autoimmune reactions, and testing various monoclonal antibody preparations for efficacy in clinical trials. Even partial success in slowing the progression of this disease can have considerable societal and economic impact. Furthermore, verification of the amyloid hypothesis will encourage development of a number of other anti-amyloid therapies that may synergize with the immunotherapeutic approach.