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Can Alzheimer disease be prevented by amyloid-β immunotherapy?

Nature Reviews Neurology volume 6, pages 108–119 (2010)Cite this article

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A Correction to this article was published on 01 June 2010

A Correction to this article was published on 01 April 2010

Abstract

Alzheimer disease (AD) is the most common form of dementia. The amyloid-β (Aβ) peptide has become a major therapeutic target in AD on the basis of pathological, biochemical and genetic evidence that supports a role for this molecule in the disease process. Active and passive Aβ immunotherapies have been shown to lower cerebral Aβ levels and improve cognition in animal models of AD. In humans, dosing in the phase II clinical trial of the AN1792 Aβ vaccine was stopped when ∼6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. As a result of this study, at least seven passive Aβ immunotherapies are now in clinical trials in patients with mild to moderate AD. Several second-generation active Aβ vaccines are also in early clinical trials. On the basis of preclinical studies and the limited data from clinical trials, Aβ immunotherapy might be most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from Aβ immunization.

Key Points

  • Preclinical studies support the idea that Alzheimer disease (AD) can be prevented by amyloid-β (Aβ) immunotherapies

  • Adverse events, but some efficacy, were observed in clinical trials of the AN1792 Aβ vaccine and the passive Aβ immunotherapy bapineuzumab

  • At least 13 Aβ immunotherapies are in clinical trials in patients with mild to moderate AD

  • Second-generation Aβ vaccines that avoid the adverse events observed with AN1792 and improve antibody generation might improve Aβ immunotherapy efficacy

  • Aβ immunization might be considerably more efficacious in AD if administered before Aβ aggregation, thereby protecting the brain from downstream neurodegenerative effects

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Figure 1: Active and passive immunization approaches.
Figure 2: Neuropathological findings in an AN1792-immunized patient with Alzheimer disease.

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Acknowledgements

The authors would like to thank Douglas Galasko (UCSD, La Jolla, CA, USA) for his helpful comments and Anahit Ghochikyan (Institute for Molecular Medicine, Huntington Beach, CA, USA) for her help in the design of Figure 1. This work was supported by NIH grants to C. A. Lemere (RO1AG20159) and E. Masliah (AG5131, AG18440, AG02074 and AG10435).

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Authors and Affiliations

  1. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, New Research Building 636F, 77 Avenue Louis Pasteur, Boston, 02115, MA, USA

    Cynthia A. Lemere

  2. Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0624, CA, USA

    Eliezer Masliah

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  1. Cynthia A. Lemere
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Correspondence to Cynthia A. Lemere.

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C. A. Lemere has received research support from Elan and Wyeth. E. Masliah declares no competing interests.

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Lemere, C., Masliah, E. Can Alzheimer disease be prevented by amyloid-β immunotherapy?. Nat Rev Neurol 6, 108–119 (2010). https://doi.org/10.1038/nrneurol.2009.219

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