Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly

Sarah Westwood, Emanuela Leoni, Abdul Hye, Steven Lynham, Mizanur R. Khondoker, Nicholas J. Ashton, Steven J. Kiddle, Alison L. Baird, Ricardo Sainz-Fuertes, Rufina Leung, John Graf, Cristina Tan Hehir, David Baker, Cristina Cereda, Chantal Bazenet, Malcolm Ward, Madhav Thambisetty, Simon Lovestone

Research output: Contribution to journalArticle

Abstract

Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

Original languageEnglish
Pages (from-to)561-572
Number of pages12
JournalJournal of Alzheimer's Disease
Volume52
Issue number2
DOIs
Publication statusPublished - May 10 2016

Keywords

  • Alzheimer's disease
  • amyloid
  • biological markers
  • blood
  • plasma
  • preclinical
  • proteomics

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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  • Cite this

    Westwood, S., Leoni, E., Hye, A., Lynham, S., Khondoker, M. R., Ashton, N. J., Kiddle, S. J., Baird, A. L., Sainz-Fuertes, R., Leung, R., Graf, J., Hehir, C. T., Baker, D., Cereda, C., Bazenet, C., Ward, M., Thambisetty, M., & Lovestone, S. (2016). Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly. Journal of Alzheimer's Disease, 52(2), 561-572. https://doi.org/10.3233/JAD-151155