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

Article type: Research Article

Authors: Westwood, Sarah^{a; b} | Leoni, Emanuela^{b; c; d} | Hye, Abdul^b | Lynham, Steven^e | Khondoker, Mizanur R.^{b; f} | Ashton, Nicholas J.^b | Kiddle, Steven J.^g | Baird, Alison L.^a | Sainz-Fuertes, Ricardo^{b; h} | Leung, Rufina^b | Graf, Johnⁱ | Hehir, Cristina Tanⁱ | Baker, David^j | Cereda, Cristina^d | Bazenet, Chantal^b | Ward, Malcolm^e | Thambisetty, Madhav^k | Lovestone, Simon^{a; *}

Affiliations: [a] Department of Psychiatry, University of Oxford, Oxford, UK | [b] King’s College London, Institute of Psychiatry, Psychology and Neuroscience, and 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 Brain and Behavioural Science, University of Pavia, Pavia, Italy | [d] Laboratory of Experimental Neurobiology, “C. Mondino” National Institute of Neurology Foundation, Pavia, Italy | [e] Proteomics Core Facility, Centre of Excellence for Mass Spectrometry, Institute of Psychiatry, Kings College London, London, UK | [f] Department of Applied Health Research, University College London, London, UK | [g] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK | [h] Partnerships in Care, North London Clinic, London, UK | [i] Diagnostics, Imaging and Biomedical Technologies, GE Global Research, Niskayuna, NY, USA | [j] Janssen R&D, Neurosciences, Titusville, NJ, USA | [k] Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Ageing, Baltimore, MD, USA

Correspondence: [*] Correspondence to: Simon Lovestone, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK. Tel.: +44 01865 223910; Fax: +44 01865 793101; E-mail: simon.lovestone@psych.ox.ac.uk.

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.

Keywords: KeywordsAlzheimer’s disease, amyloid, biological markers, blood, plasma, preclinical, proteomics

DOI: 10.3233/JAD-151155

Journal: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 561-572, 2016