OPINION Immunotherapy for Alzheimer disease-the challenge of adverse effects

Amyloid-beta (A beta) plays a crucial part in the pathogenesis of Alzheimer disease (AD), making this peptide an attractive therapeutic target. However, clearance of brain A beta in clinical trials of A beta-specific antibodies did not improve cognition in patients with AD, leading to reassessment of the current therapeutic strategies. Moreover, current immunotherapies are associated with autoimmunity-related adverse effects, and mobilization of neurotoxic insoluble A beta-oligomers. Despite the fact that antibodies to the N-terminal domain of A beta can promote A beta production, immunotherapies in ongoing clinical trials predominantly target this peptide region. Here, we address the challenges of adverse effects of immunotherapy for AD. We discuss available evidence regarding the mechanisms of both endogenous and exogenous A beta-specific antibodies, with a view to developing optimal immunotherapy based on peripheral A beta clearance, targeting of the toxic domain of A beta, and improvement of antibody specificity. Such strategies should help to make immunotherapy a safe and efficacious disease-modifying treatment option for AD.