Background: The ε4 allele of the apolipoprotein E (APOE) gene is a high-risk factor for Alzheimer's disease (AD). However, approximately 25%–40% of patients with AD do not carry the APOEe4 allele, and the pathophysiological mechanisms underlying AD are less evident in these individuals. The main objective of this study was to understand the changes in plasma that may contribute to disease pathogenesis in AD and how APOEe3 and APOEe4 contribute to plasma biomarker profiles in AD.
Methods: We conducted an in-depth plasma proteomics analysis using intensive depletion of high-abundant plasma proteins with Agilent multiple affinity removal liquid chromatography (LC) column- Human 14 (Hu14) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) technique coupled with Q-Exactive Plus mass spectrometer (Thermo Electron, Bremen, Germany). Two search engines were used to analyze the raw files, including ProteomeDiscoverer v2.4 (Thermo Fisher Scientific, Waltham, MA) and Scaffold Q+ software v 4.11.0 (Proteome Software, Portland).
Results: In our study, we have expanded the depth of plasma proteome coverage to reveal new differentially expressed proteins (DEPs) that correlated with AD pathogensis. The identification of 134 proteins in AD APOEε3 relative to ε3 controls and 71 in AD APOEε4 relative to ε4 controls are reported in this study. Mainly signature proteins identified were associated with molecular functions including complement cascade, glycolysis, metabolism, plasma lipoprotein assembly, remodeling, and clearance. Here, we have shown a list of proteins such as MB, GPI and PKM reflecting the biochemical changes that are associated with pathogenesis of AD despite the APOE genotypes. The increase plasma proteome depth allowed us to identify a large number of proteins which are previously reported in brain tissue or cerebrospinal fluid in AD cohorts are likely much stronger candidates for future validation work.
Conclusion: This study performed an in-depth proteome analysis to identify plasma proteome signatures associated with APOEε3 and APOEε4 genotypes. Further analysis of proteome correlation with APOE genotpyes will yield clinically meaningful information into the biological basis of AD.