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

Abstract

The e4 allele of the apolipoprotein E (APOE) gene is a high-risk factor for Alzheimer's disease (AD). However, approximately 25% to 40% of patients with AD do not carry the APOE e4 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 APOE e3 and APOE e4 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 APOE e3 and APOE e4 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 APOE e3 and APOE e4 genotypes depicting the involvement of these proteins in the pathogenesis of AD regardless of the APOE genotypes. We also compared the plasma proteomes of e4 and e3 carriers in normal controls, which provided insight into factors that may provide protection from progression to AD despite the presence of the e4 allele. Furthermore, our findings also identified some proteins previously discovered in AD CSF and brain proteomics signatures that could provide clinically meaningful information.

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

“…Finally, Patel et al recently analyzed fresh human surgical tissue from tumor or epileptogenic adjacent regions using scRNAseq. In line with our findings, they identified several WGCNA modules associated with age, sex and APOE4 that were enriched for genes involved in lipid and carbohydrate metabolism 83 , a finding also reflected at the protein level by several large proteomics studies implicating immunometabolism in cortex 7,84,85 , CSF 7,86,87 , plasma 88 , and in isolated microglia 89 .…”

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

“…Many potentially modifiable AD risk factors, such as obesity, diabetes, and physical inactivity, also converge on immunometabolic pathways, as do other prominent genetic risk factors, such as TREM2, 84 CLU , 85 , 86 and BHLHE40. 87 In addition, a recent study identified several WGCNA modules associated with APOE4 that were enriched for genes involved in lipid and carbohydrate metabolism, 88 a finding also reflected at the protein level by several large proteomics studies in cortex, 7 , 89 , 90 cerebrospinal fluid (CSF), 7 , 91 , 92 plasma, 93 and isolated microglia. 94 Thus, viewing AD through the lens of immunometabolism holds promise to fuse these seemingly disparate risk factors into a comprehensive mechanism whereby impaired microglial metabolism triggers chronic neuroinflammation, sparking the neurodegenerative cascade.…”