Open questions for Alzheimer's disease immunotherapy

Perhaps more definitively than any other class of novel Alzheimer's disease (AD) therapy, pre-clinical studies in mouse models of amyloid β (Aβ) deposition have established the disease-modifying potential of anti-Aβ immunotherapy. Despite disappointing results to date from anti-Aβ immunotherapy therapeutic trials, there is continued hope that such immunotherapies, especially if used in the preclinical stages, could prove to be the first disease-modifying therapies available for AD. The general optimism that Aβ-targeting and emerging tau-targeting immunotherapies may prove to be disease modifying is tempered by many unanswered questions regarding these therapeutic approaches, including but not limited to i) lack of precise understanding of mechanisms of action, ii) the factors that regulate antibody exposure in the brain, iii) the optimal target epitope, and iv) the mechanisms underlying side effects. In this review I discuss how answering these and other questions could increase the likelihood of therapeutic success. As passive immunotherapies are also likely to be extremely expensive, I also raise questions relating to cost-benefit of biologic-based therapies for AD that could limit future impact of these therapies by limiting access due to economic constraints.