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Immunotherapy for Alzheimer disease—the challenge of adverse effects

Nature Reviews Neurology volume 8, pages 465–469 (2012)Cite this article

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Abstract

Amyloid-β (Aβ) plays a crucial part in the pathogenesis of Alzheimer disease (AD), making this peptide an attractive therapeutic target. However, clearance of brain Aβ in clinical trials of Aβ-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 Aβ-oligomers. Despite the fact that antibodies to the N-terminal domain of Aβ can promote Aβ 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 Aβ-specific antibodies, with a view to developing optimal immunotherapy based on peripheral Aβ clearance, targeting of the toxic domain of Aβ, and improvement of antibody specificity. Such strategies should help to make immunotherapy a safe and efficacious disease-modifying treatment option for AD.

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Figure 1: Adverse effects associated with Alzheimer disease immunotherapy.
Figure 2: Epitopes of the amyloid-β (Aβ) peptide sequence.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant no. 30973144) and the Natural Science Foundation Project of CQCSTC (grant no. CSTC2010BA5004). The authors thank N. Wei at Daping Hospital of Third Military Medical University for assistance with creating the figures.

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Authors and Affiliations

  1. Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital and Institute of Field Surgery, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China

    Yu-Hui Liu, Hua-Dong Zhou & Yan-Jiang Wang

  2. Department of Psychiatry and Behavioral Neurosciences, Neuroimmunology Laboratory, Morsani College of Medicine, University of South Florida, 3515 East Fletcher Avenue, MDT 14, Tampa, 33613, FL, USA

    Brian Giunta

  3. Department of Psychiatry and Behavioral Neurosciences, Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, 3515 East Fletcher Avenue, MDT 14, Tampa, 33613, FL, USA

    Jun Tan

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All authors contributed to researching data for the article, discussion of the content, writing the article, and review and/or editing of the manuscript before submission. Y.-H. Liu, B. Giunta and H.-D. Zhou contributed equally to this work.

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Correspondence to Yan-Jiang Wang.

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Liu, YH., Giunta, B., Zhou, HD. et al. Immunotherapy for Alzheimer disease—the challenge of adverse effects. Nat Rev Neurol 8, 465–469 (2012). https://doi.org/10.1038/nrneurol.2012.118

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