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Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis

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Abstract

The amyloid cascade hypothesis of Alzheimer’s disease (AD) is testable: it implies that interference with Aβ aggregation and plaque formation may be therapeutically useful. Aβ42 immunisation of amyloid precursor protein (APP) transgenic mice prevented plaque formation and caused removal of existing plaques. The first clinical studies of Aβ immunisation in AD patients (AN1792, Elan Pharmaceuticals) were halted when some patients suffered side effects. Since our confirmation that Aβ immunisation can prompt plaque removal in human AD, we have performed a clinical and neuropathological follow up of AD patients in the initial Elan Aβ immunisation trial. In immunised AD patients, we found: a lower Aβ load, with evidence that plaques had been removed; a reduced tau load in neuronal processes, but not in cell bodies; and no evidence of a beneficial effect on synapses. There were pathological “side effects” including: increased microglial activation; increased cerebral amyloid angiopathy; and there is some evidence for increased soluble/oligomeric Aβ. A pathophysiological mechanism involving effects on the cerebral vasculature is proposed for the clinical side effects observed with some active and passive vaccine protocols. Our current knowledge of the effects of Aβ immunotherapy is based on functional information from the early clinical trials and a few post mortem cases. Several further clinical studies are underway using a variety of protocols and important clinical, imaging and neuropathological data will become available in the near future. The information obtained will be important in helping to understand the pathogenesis not only of AD but also of other neurodegenerative disorders associated with protein aggregation.

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Acknowledgments

We thank the patients who were involved in this study and their carers. Vivienne Hopkins, David Wilkinson, Anthony Bayer, Roy Jones and Roger Bullock enrolled patients in the original trial and facilitated subsequent follow up of the patients. The Neuropathology Section, Department of Cellular Pathology, Southampton University Hospitals NHS Trust and the Histopathology Research Unit and Biomedical Research Unit of the School of Medicine, University of Southampton and Miss Elina Zotova facilitated tissue analysis. Staff at Elan Pharmaceuticals made available original clinical trial data. The studies were funded by the Alzheimer Research Trust (JARN, DB, CH: ART/PG2006/4) and the Medical Research Council (DB: G0501033).

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Authors and Affiliations

  1. Division of Clinical Neurosciences, School of Medicine, Southampton General Hospital, University of Southampton, Mailpoint 806, Southampton, SO16 6YD, UK

    Delphine Boche, Nathan Denham, Clive Holmes & James A. R. Nicoll

  2. M.A.R.C., Moorgreen Hospital, Hampshire Partnership Foundation, Southampton, UK

    Clive Holmes

  3. Department of Cellular Pathology, Southampton University Hospitals NHS Trust, Southampton, UK

    James A. R. Nicoll

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  1. Delphine Boche
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  2. Nathan Denham
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  3. Clive Holmes
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  4. James A. R. Nicoll
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Correspondence to Delphine Boche.

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Boche, D., Denham, N., Holmes, C. et al. Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis. Acta Neuropathol 120, 369–384 (2010). https://doi.org/10.1007/s00401-010-0719-5

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  • DOI: https://doi.org/10.1007/s00401-010-0719-5

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