# A Robust Serum Proteomic Signature of the E2 Allele of Apolipoprotein E

## TL;DR

The study identifies a serum protein signature linked to the APOE e2 allele, highlighting its role in lipid regulation and inflammation, and suggests new therapeutic targets for Alzheimer's disease.

## Contribution

The study expands and validates a serum protein signature of the APOE e2 allele using multiple proteomic platforms and UK Biobank data.

## Key findings

- APOE genotypes are robustly associated with serum levels of APOE and a complex of apolipoproteins.
- Neutrophil-secreted granule proteins like CAMP, CTSG, DEFA3, and MPO are linked to APOE genotypes.
- Inhibition of OLFM4 is proposed as a new therapeutic target for Alzheimer's disease.

## Abstract

A signature of 16 serum proteins that were previously profiled using the aptamer‐based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass‐spectrometry, ELISA, Luminex, blood transcriptomics, and antibody‐based Olink serum proteomics. Some of the findings were replicated in the UK Biobank using antibody‐based Olink serum proteomics. This analysis replicated the association between APOB and the e2 allele of APOE, detected a new, robust pattern of association between APOE genotypes and the serum level of APOE, and discovered new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC2, APOC3, APOC4, APOE, APOF, and APOL1. In addition, 13 new proteins correlated with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease.

This study expands a serum protein signature of the e2 allele of APOE using multiple proteomic platforms and UK Biobank replication. The signature supports the role of APOE in lipid regulation through apolipoproteins and inflammation and includes, among others, neutrophil secreted granule proteins CAMP, CTSG, DEFA3, and MPO that point to inhibition of OLFM4 as a target for Alzheimer's disease therapeutics.