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Brain 2006 129(11):3042-3050; doi:10.1093/brain/awl279
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Proteome-based plasma biomarkers for Alzheimer's disease

A. Hye1, S. Lynham1, M. Thambisetty1, M. Causevic1, J. Campbell3, H. L. Byers3, C. Hooper1, F. Rijsdijk2, S. J. Tabrizi4, S. Banner1, C. E. Shaw1, C. Foy1, M. Poppe1, N. Archer1, G. Hamilton1, J. Powell1, R. G. Brown1, P. Sham2, M. Ward3 and S. Lovestone1

1 King's College London, MRC Centre for Neurodegeneration Research London, UK 2 King's College London, MRC Social, Genetic and Developmental Psychiatry Centre London, UK 3 Proteome Sciences Plc, Institute of Psychiatry London, UK 4 University College London, Institute of Neurology London, UK

Correspondence to: Simon Lovestone, PhD, King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK E-mail: s.lovestone{at}iop.kcl.ac.uk

Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case–control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls. For discovery-phase proteomics analysis, 50 people with Alzheimer's dementia were recruited through secondary services and 50 normal elderly controls through primary care. For validation purposes a total of 511 subjects with Alzheimer's disease and other neurodegenerative diseases and normal elderly controls were examined. Image analysis of the protein distribution of the gels alone identifies disease cases with 56% sensitivity and 80% specificity. Mass spectrometric analysis of the changes observed in two-dimensional electrophoresis identified a number of proteins previously implicated in the disease pathology, including complement factor H (CFH) precursor and {alpha}-2-macroglobulin ({alpha}-2M). Using semi-quantitative immunoblotting, the elevation of CFH and {alpha}-2M was shown to be specific for Alzheimer's disease and to correlate with disease severity although alternative assays would be necessary to improve sensitivity and specificity. These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as {alpha}-2M may be a specific markers of this illness.

Key Words: biomarkers; two-dimensional gel electrophoresis (2-DGE); plasma; Alzheimer's disease; proteomics

Abbreviations: AMD, age-related macular degeneration; {alpha}-2M, {alpha}-2-macroglobulin; CFH, complement factor H; FDR, false discovery rate; 2-DGE, two-dimensional gel electrophoresis

Received July 31, 2006. Revised August 23, 2006. Accepted September 1, 2006.


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