Impact of APOE ε3 and ε4 genotypes on plasma proteome signatures in Alzheimer’s disease

Abstract

AbstractThe 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 APOEε4 allele, and the pathophysiological mechanisms underlying AD are less evident in these individuals. The main objective of this study was to understand better the changes in plasma that may contribute to disease pathogenesis in AD and how APOEε3 and APOEε4 contribute to biomarker profiles in AD. We conducted an in-depth plasma proteomics analysis using intensive depletion of high-abundant plasma proteins using the Agilent multiple affinity removal liquid chromatography (LC) column-Human 14 (Hu14) followed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS PAGE) technique. In this study, we identified a high number of protein expression alterations in plasma which were found uniquely in APOEε3 and APOEε4 carriers. These differentially expressed proteins (DEPs) were associated with several molecular functions, including complement cascade, glycolysis, metabolism, plasma lipoprotein assembly, remodelling, and clearance. In addition to unique changes in both APOE genotypes, many proteins were also dysregulated in the presence of both APOEε3 and APOEε4 genotypes depicting the involvement of these proteins in the pathogenesis of AD regardless of the APOE genotypes. We also compared the plasma proteomes of ε4 and ε3 carriers in normal controls, which provided insight into factors that may provide protection from progression to AD despite the presence of the ε4 allele. Furthermore, our findings also identified some proteins previously discovered in AD CSF and brain proteomics signatures that could provide clinically meaningful information.