Plasma Protein Profiling of Mild Cognitive Impairment and Alzheimer's Disease Across Two Independent Cohorts

Article type: Research Article

Authors: Muenchhoff, Julia^a | Poljak, Anne^{a; b; c} | Song, Fei^a | Raftery, Mark^b | Brodaty, Henry^a | Duncan, Mark^{e; f; g} | McEvoy, Mark^h | Attia, John^h | Schofield, Peter W.^{h; i} | Sachdev, Perminder S.^{a; d; *}

Affiliations: [a] Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia | [b] Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, Australia | [c] School of Medical Sciences, University of New South Wales, Sydney, Australia | [d] Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia | [e] Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Denver-School of Medicine, Aurora, Colorado, USA | [f] Biodesix Inc., Boulder, Colorado, USA | [g] Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia | [h] School of Medicine and Public Health, University of Newcastle, Newcastle, Australia | [i] School of Psychology, University of Newcastle, Newcastle, Australia

Correspondence: [*] Correspondence to: Perminder S. Sachdev, NPI, Euroa Centre, Barker Street, Randwick, NSW 2031, Australia. Tel.: +61 2 9382 3763; Fax: +61 29382 3774; E-mail: [email protected].

Abstract: To unlock the full potential of disease modifying treatments, it is essential to develop early biomarkers for Alzheimer's disease (AD). For practical reasons, blood-based markers that could provide a signal at the stage of mild cognitive impairment (MCI) or even earlier would be ideal. Using the proteomic approach of isobaric tagging for relative and absolute quantitation (iTRAQ), we compared the plasma protein profiles of MCI, AD, and cognitively normal control subjects from two independent cohorts: the Sydney Memory and Ageing Study (261 MCI subjects, 24 AD subjects, 411 controls) and the Hunter Community Study (180 MCI subjects, 153 controls). The objective was to identify any proteins that are differentially abundant in MCI and AD plasma in both cohorts, since they might be of interest as potential biomarkers, or could help direct future mechanistic studies. Proteins representative of biological processes relevant to AD pathology, such as the complement system, the coagulation cascade, lipid metabolism, and metal and vitamin D and E transport, were found to differ in abundance in MCI. In particular, levels of complement regulators C1 inhibitor and factor H, fibronectin, ceruloplasmin, and vitamin D-binding protein were significantly decreased in MCI participants from both cohorts. Several apolipoproteins, including apolipoprotein AIV, B-100, and H were also significantly decreased in MCI. Most of these proteins have previously been reported as potential biomarkers for AD; however, we show for the first time that a significant decrease in plasma levels of two potential biomarkers (fibronectin and C1 inhibitor) is evident at the MCI stage.

Keywords: Alzheimer's disease, apolipoproteins, biomarkers, complement system proteins, fibrinogen, fibronectin, mild cognitive impairment, plasma, proteomics, vitamin D-binding protein

DOI: 10.3233/JAD-141266

Journal: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1355-1373, 2015