Proteome-Based Plasma Markers of Brain Amyloid-β Deposition in Non-Demented Older Individuals

Article type: Research Article

Authors: Thambisetty, Madhav^{a; 1; *} | Tripaldi, Romina^{b; 1} | Riddoch-Contreras, Joanna^{b; 1} | Hye, Abdul^b | An, Yang^a | Campbell, James^c | Sojkova, Jitka^a | Kinsey, Anna^b | Lynham, Steven^b | Zhou, Yun^d | Ferrucci, Luigi^e | Wong, Dean F.^d | Lovestone, Simon^{b; 1} | Resnick, Susan M.^{a; 1}

Affiliations: [a] National Institute on Aging, Baltimore, MD, USA | [b] Institute of Psychiatry, London, UK | [c] Proteome Sciences plc, London, UK | [d] Department of Radiology, Johns Hopkins University, Baltimore, MD, USA | [e] Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA

Correspondence: [*] Correspondence to: Madhav Thambisetty, MD, PhD, Room 4B-311, 251 Bayview Blvd, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD 21224, USA. Tel.: +1 410 558 8572; Fax: +1 410 558 8674; E-mail: [email protected].

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

Abstract: Blood-based markers reflecting core pathological features of Alzheimer's disease (AD) in pre-symptomatic individuals are likely to accelerate the development of disease-modifying treatments. Our aim was to discover plasma proteins associated with brain amyloid-β (Aβ) burden in non-demented older individuals. We performed discovery-phase experiments using two dimensional gel electrophoresis (2DGE) and mass spectrometry-based proteomic analysis of plasma in combination with 11C-PiB PET imaging of the brain in samples collected 10 years prior to the PET scans. Confirmatory studies used ELISA assays in a separate set of blood samples obtained within a year of the PET scans. We observed that a panel of 18 2DGE plasma protein spots effectively discriminated between individuals with high and low brain Aβ. Mass spectrometry identified these proteins, many of which have established roles in Aβ clearance, including a strong signal from apolipoprotein-E (ApoE). In validation-phase studies, we observed a strong association between plasma ApoE concentration and Aβ burden in the medial temporal lobe. Targeted voxel-based analysis localized this association to the hippocampus and entorhinal cortex. APOE ε4 carriers also showed greater Aβ levels in several brain regions relative to ε4 non-carriers. These results suggest that both peripheral concentration of ApoE protein and APOE genotype are related to early neuropathological changes in brain regions vulnerable to AD pathology even in the non-demented elderly. Our strategy combining proteomics with in vivo brain amyloid imaging holds promise for the discovery of biologically relevant peripheral markers in those at risk for AD.

Keywords: Alzheimer's disease, amyloid-β, biomarker, brain, plasma, proteomics

DOI: 10.3233/JAD-2010-101350

Journal: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1099-1109, 2010