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

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.

Kallikrein‐8 inhibition attenuates Alzheimer's disease pathology in mice

“…Two of these proteins, that is, fibronectin and steroid 5 alpha-reductase 1 (Srd5a1), play a role in AD and are therefore candidates for further testing in the context of anti-KLK8 therapy. Cerebral fibronectin levels are reduced already before AD onset in patients with mild cognitive impairment [38]. Moreover, fibronectin promotes the secretion of APP and impedes APP integration into plasma membranes and subsequent Ab biogenesis [39].…”

Early changes in extracellular matrix in Alzheimer's disease

“…Conversely, no significant difference was seen in perlecan mRNA levels in the hippocampus in AD when compared to age‐matched controls, indicating that perlecan expression may remain stable in AD . In the case of fibronectin, it has been previously reported that high molecular fibronectin forms appear more frequently and at higher amounts in plasma in AD than in age‐matched controls , and that levels of plasma fibronectin are higher in AD than in healthy controls and individuals with mild cognitive impairment . On the other hand, unchanged plasma fibronectin concentrations have also been described in AD .…”

Serping1/C1 Inhibitor Affects Cortical Development in a Cell Autonomous and Non-cell Autonomous Manner

“…Expression of multiple components of the complement pathway, including C1 inhibitor has also been demonstrated in Alzheimer's disease, which may reflect ongoing inflammation in the brains of the patients (Walker et al, 1995; Veerhuis et al, 1998; Yasojima et al, 1999). It has been suggested that reduced levels of C1 inhibitor may be a biomarker for Alzheimer's disease (Akuffo et al, 2008; Cutler et al, 2008; Chiam et al, 2015; Muenchhoff et al, 2015; Morgan et al, 2017). …”