Evaluation of a plasma protein panel as a compound biomarker for Alzheimers disease

Lead Research Organisation: King's College London
Department Name: Unlisted

Abstract

Alzheimer?s disease is one of the most common and devastating of diseases of the elderly. As the population ages then the costs, already larger than cancer and heart disease combined, are set to rise substantially. Progress is being made in understanding the disease pathogenesis with the first disease modifying trials being reported this year. However, despite this progress, Alzheimer?s remains difficult to diagnose in the early stages, impossible to predict and even monitoring disease progression is difficult and subject to day to day variation and other sources of error. One way of overcoming these problems is the use of tests or biomarkers. Many such tests in development are dependent on access to sophisticated brain scanning or spinal fluid. We have taken an alternative approach in seeking blood based biomarkers. Studies in our laboratories over the past five years have revealed a set of markers that differ between Alzheimer?s patients and other elderly people. We propose now to develop these further into a test and then to trial this test on a large number of people. We will determine in this way, whether these proteins, together or separately, do function as a test in Alzheimer?s disease either for early diagnosis, for prediction of dementia or for monitoring disease progression. If they do, and the evidence so far is promising, then this has the potential to substantially improve diagnosis and to make trials of drugs for Alzheimer?s faster and more accurate to perform.

Technical Summary

Using gel based proteomics we have identified a panel of potential plasma biomarkers for Alzheimer?s disease. These proteins have been replicated in moderately large subject populations of 200-500 subjects and subsequently the same proteins or closely related proteins have been identified in similar, independent studies, including those of our collaborators. These proteins together show promise as a compound marker for Alzheimer?s disease ? for example a sub-set of just five of the proteins predict brain volume, a marker of disease, in 80% of subjects. Having replicated, or partially validated, this set of proteins we now need to develop a stable and fully quantitative and sensitive assay and to test this on very large numbers of subjects, including population based cohorts. We plan to develop dual immunocapture and mass spectrometry based multiplexed assays and in a staged design determine the characteristics of the resulting compound assay as a marker of diagnosis, prediction and progression. We have, through this collaborative group, assembled a very large set of well characterised subjects for such studies including the main US and European AD Biomarker collections and population based sample sets including the MRC CFAS study. The study led by the MRC Centre for Neurodegeneration brings together expertise in Alzheimer?s disease, in assay design and development, in population based analyses and in statistics. The set of markers we have developed to date are, to our knowledge, the best characterised set developed through proteomics and are ready for further development and translation to clinical utility.

Publications

10 25 50
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Ashton NJ (2015) Blood protein predictors of brain amyloid for enrichment in clinical trials? in Alzheimer's & dementia (Amsterdam, Netherlands)

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Baird AL (2015) Blood-Based Proteomic Biomarkers of Alzheimer's Disease Pathology. in Frontiers in neurology

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Hakobyan S (2016) Complement Biomarkers as Predictors of Disease Progression in Alzheimer's Disease. in Journal of Alzheimer's disease : JAD

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Henriksen K (2014) The future of blood-based biomarkers for Alzheimer's disease. in Alzheimer's & dementia : the journal of the Alzheimer's Association

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Hye A (2014) Plasma proteins predict conversion to dementia from prodromal disease. in Alzheimer's & dementia : the journal of the Alzheimer's Association

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Lunnon K (2013) A blood gene expression marker of early Alzheimer's disease. in Journal of Alzheimer's disease : JAD

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Menni C (2015) Circulating Proteomic Signatures of Chronological Age. in The journals of gerontology. Series A, Biological sciences and medical sciences

 
Description Alzheimer's society studentships
Amount £75,000 (GBP)
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 10/2014
 
Description IMI EMIF
Amount € 48,000,000 (EUR)
Funding ID 115372 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 12/2012 
End 12/2017
 
Description Not applicable (possibly confidential)
Amount £7,000,000 (GBP)
Funding ID CONFIDENTIAL INFORMATION 
Organisation University of Leicester 
Department John and Lucille van Geest Foundation
Sector Academic/University
Country United Kingdom
Start 04/2013 
 
Description Strategic Awards - Neuroinflammation consortium
Amount £5,000,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 01/2020
 
Description Collaboration with Calum Sutherland 
Organisation University of Dundee
Country United Kingdom 
Sector Academic/University 
PI Contribution New grant: PRELIMINARY EVALUATION OF THE THERAPEUTIC POTENTIAL OF LITHIUM IN MILD COGNITIVE IMPAIRMENT Funded by CSO Scotland Shared study to explore further therapeutic potential of lithium and target engagement biomarkers for AD
Collaborator Contribution New grant: PRELIMINARY EVALUATION OF THE THERAPEUTIC POTENTIAL OF LITHIUM IN MILD COGNITIVE IMPAIRMENT Funded by CSO Scotland Shared study to explore further therapeutic potential of lithium and target engagement biomarkers for AD
Impact Clinical and biochemical expertise
Start Year 2015
 
Description Collaboration with Fraunhofer and AETIONOMY 
Organisation Fraunhofer Society
Department Fraunhofer Institute for Algorithms and Scientific Computing
Country Germany 
Sector Public 
PI Contribution We have established a collaboration with Martin Hoffmann-Apitius at Fraunhofer SCAI with funding from UCB via the AETIONOMY programme. The funding is an estimate at present and is for a post-doctoral research worker for two years. The collaboration is to utilise the datasets we have generated together with our access to and knowledge of EHRs. We will also contribute informatics expertise and deep learning/neural networks to the collaboration. UPDATE JAN 2018; we have also agreed to share biomolecular data including proteomics with our partners in Fraunhofer, extending our collaboration and leveraging resources from both sites to accelerate our understanding of AD and PD and developing novel biomarkers
Collaborator Contribution The Franunhofer / AETIONOMY group have generated a systems approach to determining pathways and mechanisms in neurodegeneration and we will work together utilising their Big Data analytics and tools and our Neural Networks/NLP approach and data to validate and extend their models.
Impact Too soon for outcomes
Start Year 2016
 
Description DPUK Biomarkers 
Organisation Araclon Biotech
Country Spain 
Sector Private 
PI Contribution Based on the biomarker work we have developed, the companies MSD, Araclon and SomaLogic have joined as partners to Dementias Platform UK. The specific biomarkers we have developed and published will be implemented now on the MSD platform and using this and SomaLogic platform tested for validation in the DPUK
Collaborator Contribution Based on the biomarker work we have developed, the companies MSD, Araclon and SomaLogic have joined as partners to Dementias Platform UK. The specific biomarkers we have developed and published will be implemented now on the MSD platform and using this and SomaLogic platform tested for validation in the DPUK
Impact N/A
Start Year 2016
 
Description DPUK Biomarkers 
Organisation Meso Scale Delivery
Country United States 
Sector Public 
PI Contribution Based on the biomarker work we have developed, the companies MSD, Araclon and SomaLogic have joined as partners to Dementias Platform UK. The specific biomarkers we have developed and published will be implemented now on the MSD platform and using this and SomaLogic platform tested for validation in the DPUK
Collaborator Contribution Based on the biomarker work we have developed, the companies MSD, Araclon and SomaLogic have joined as partners to Dementias Platform UK. The specific biomarkers we have developed and published will be implemented now on the MSD platform and using this and SomaLogic platform tested for validation in the DPUK
Impact N/A
Start Year 2016
 
Description DPUK Biomarkers 
Organisation SomaLogic
Country United States 
Sector Private 
PI Contribution Based on the biomarker work we have developed, the companies MSD, Araclon and SomaLogic have joined as partners to Dementias Platform UK. The specific biomarkers we have developed and published will be implemented now on the MSD platform and using this and SomaLogic platform tested for validation in the DPUK
Collaborator Contribution Based on the biomarker work we have developed, the companies MSD, Araclon and SomaLogic have joined as partners to Dementias Platform UK. The specific biomarkers we have developed and published will be implemented now on the MSD platform and using this and SomaLogic platform tested for validation in the DPUK
Impact N/A
Start Year 2016
 
Description Joint collaborative studies (CONFIDENTIAL) 
Organisation General Electric
Country United States 
Sector Private 
PI Contribution A joint initiative between J&J, GEHC and KCL. We are generating new data on samples provided and together with the companies are jointly analysing our datasets as biomarkers for Alzheimer's disease. This is a substantial collaboration with bi-weekly telephone conferences and 6-monthly face to face meetings
Collaborator Contribution J&J providing data and considerable informatics time and expertise. GEHC providing samples and imaging analysis time and expertise. Funding provided by the companies to KCL in excess of £200k
Impact Multidisciplinary teams from all three partners including imaging, informatics and proteomics expertise.
Start Year 2011
 
Description Joint collaborative studies (CONFIDENTIAL) 
Organisation Johnson & Johnson
Department Neuroscience Johnson and Johnson
Country United States 
Sector Private 
PI Contribution A joint initiative between J&J, GEHC and KCL. We are generating new data on samples provided and together with the companies are jointly analysing our datasets as biomarkers for Alzheimer's disease. This is a substantial collaboration with bi-weekly telephone conferences and 6-monthly face to face meetings
Collaborator Contribution J&J providing data and considerable informatics time and expertise. GEHC providing samples and imaging analysis time and expertise. Funding provided by the companies to KCL in excess of £200k
Impact Multidisciplinary teams from all three partners including imaging, informatics and proteomics expertise.
Start Year 2011
 
Description NIA joint biomarker initiative 
Organisation National Institute on Aging
Country United States 
Sector Public 
PI Contribution We have forged a funded collaboration with the NIA (via Madhave Thambisetty) to collaborate on dementia biomarkers using the US sample collections. We provide all wet-lab and together work on informatics analysis
Collaborator Contribution Samples, PI time, intellectual engagement, finding
Impact Ongoing collaborations with multiple publications
Start Year 2011
 
Description SomaLogic Centre of Excellence at Oxford 
Organisation SomaLogic
Country United States 
Sector Private 
PI Contribution Following a long collaborative relationship forged through biomarker studies in AD and PD and studies of mechanisms in cellular models, we have agreed to establish a Centre of Excellence at Oxford with SomaLogic including establishing a laboratory and accelerating both sample analysis and use of the data to progress experimental medicine and translational research
Collaborator Contribution SomaLogic will bring investment to establish and manage a laboratory on site in the translational research campus at Oxford and act as a hub for proteomic studies using aptamer capture. Specifically in relation to our collaboration SomaLogic will bring their most advanced and extensive assay to very large studies in mental health and in neurodegeneration to our collaboration
Impact No outcomes to date; programme completed contractural agreements in 2017 and will inititate in 2018
Start Year 2017
 
Title Alzheimer's Plasma 9-plex Assay 
Description See http://www.proteomics.com/products-and-services/cns/alzheimer-s-plasma-9-plex Developed jointly with KCL directly as a consequence of MRC funding 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact Considerable impact in the course of development including further funding 
URL http://www.proteomics.com/products-and-services/cns/alzheimer-s-plasma-9-plex
 
Description WHO Bulletin Interview with Carol 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview with Carol Brayne: a life-course approach to prevent dementia
https://apps.who.int/iris/handle/10665/272247
WHO Bulletin Interview with Carol
Year(s) Of Engagement Activity 2018
URL https://apps.who.int/iris/handle/10665/272247
 
Description schools and lay groups 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact This work has been incorporated into multiple public dissemination outputs

No subsequent impact
Year(s) Of Engagement Activity 2006,2007,2008,2009