Immunotherapy in Alzheimer's disease: where do we stand? Where should we go?

Alzheimer's disease (AD) is a highly prevalent neurodegenerative disease. In addition to its enormous personal and socioeconomic costs, the situation is worsened by the lack of an effective prevention and treatment. Anti-amyloid-beta (Abeta) immunization strategies showed excellent results when tested on AD transgenic models. However, clinical studies with active and passive immunotherapy have been disappointing in several aspects, especially lately, when reports analyzing long term result of immunization protocols failed to show improvement in cognitive function and disease progression. Furthermore, some of the active immunotherapy protocols appear to be associated with severe side effects, including brain inflammation and amyloid angiopathy mediated hemorrhage. However, even through detailed information on the mechanism for Abeta clearance is still missing, results are valuable for the understanding of the disease. The focus of this review is to discuss the current experience with the various types of immunotherapy tested in animal models and AD patients, and the information they provide regarding disease mechanisms. In light of those results, alternatives or conditions that could improve immunotherapy utility are analyzed. Regardless of the setbacks, immunotherapy as a combination therapy, including humoral and cell-based approaches, still holds a promise for the treatment of AD.