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Candidate Blood Proteome Markers of Alzheimer's Disease Onset and Progression: A Systematic Review and Replication Study

Article type: Research Article

Authors: Kiddle, Steven J.a; b; 1; * | Sattlecker, Martinaa; b; 1 | Proitsi, Petroulaa | Simmons, Andrewa; b | Westman, Ericc | Bazenet, Chantala | Nelson, Sally K.d | Williams, Stephend | Hodges, Angelaa | Johnston, Carolinea; b | Soininen, Hilkkae | Kłoszewska, Iwonaf | Mecocci, Patriziag | Tsolaki, Magdah | Vellas, Brunoi | Newhouse, Stephena; b | Lovestone, Simona; b | Dobson, Richard J. B.a; b; *

Affiliations: [a] King's College London, Institute of Psychiatry, London, UK | [b] NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK | [c] Department of Neurobiology, Karolinska Institutet, Care Sciences and Society, Stockholm, Sweden | [d] SomaLogic, Boulder, Colorado, USA | [e] Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland | [f] Medical University of Lodz, Lodz, Poland | [g] Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy | [h] 3rd Department of Neurology, Aristotle University, Thessaloniki, Greece | [i] INSERM University of Toulouse, Toulouse, France

Correspondence: [*] Correspondence to: Steven J. Kiddle or Richard Dobson, Box P092, De Crespigny Park, London, SE5 8AF, UK. Tel.: +44 20 7848 0924; Fax: +44 20 7848 0866; E-mails: steven.kiddle@kcl.ac.uk or richard.j.dobson@kcl.ac.uk.

Note: [1] These authors contributed equally to this manuscript.

Keywords: Alzheimer's disease, biomarkers, blood, magnetic resonance imaging, nucleotide aptamers, proteome

DOI: 10.3233/JAD-130380

Journal: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 515-531, 2014

Accepted 22 July 2013
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Published: 25 November 2013
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Abstract

A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: α-1-antitrypsin, α-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency.

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