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Aβ immunotherapy for Alzheimer’s disease: effects on apoE and cerebral vasculopathy

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Abstract

Aβ immunotherapy for Alzheimer’s disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aβ to the cerebral vasculature induced by Aβ immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aβ. ARIA occurring in some current trials of Aβ immunotherapy may reflect an extreme form of these vascular changes.

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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. Jim Neal provided 2 immunized AD cases from Cardiff and Laura Palmer at the South West Dementia Brain Bank provided the 28 non-immunized AD cases. The Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, the Histochemistry Research Unit, and the Biomedical Imaging Unit of the Faculty of Medicine, University of Southampton facilitated tissue processing, staining and analysis. Staff at Elan Pharmaceuticals made available original clinical trial data. We are grateful to Prothena Biosciences 650 Gateway Blvd, South San Francisco, CA 94080, USA, for provision of the apoE antibodies. This study was supported partially by a British Council Japan Association Scholarship to Dr. Sakai and partly by Alzheimer’s Research UK. The collection and characterization of brains in the South West Dementia Brain Bank were supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly).

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Sakai, K., Boche, D., Carare, R. et al. Aβ immunotherapy for Alzheimer’s disease: effects on apoE and cerebral vasculopathy. Acta Neuropathol 128, 777–789 (2014). https://doi.org/10.1007/s00401-014-1340-9

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