# The role of apolipoprotein E in Alzheimer's adaptive immunity

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $607,408

## Abstract

Project Summary
Apolipoprotein E (APOE) polymorphic alleles are the main genetic determinants of AD risk. An unexplored
function of ApoE in AD pathobiology is that of its role in immune modulation and susceptibility to viral infection.
T cells that initially encounter antigen in the periphery can enter the cerebrospinal fluid (CSF) via the systemic
circulation. However, the antigens underlying this process are not clear. Preliminary data shown here
demonstrates a peripheral adaptive immune signature of AD characterized by an increased number of CD8
effector T cells. Our data further indicates APOE allele-dependent differences in CD8 T effector cell numbers in
AD blood. Strikingly, CD8 effector T cells were also present in patient CSF and T cell receptor (TCR) sequencing
indicates their clonal expansion against the Epstein-Barr virus (EBV) BZLF1 antigen. Further, analysis of CSF
TCR sequences indicates increased CD8 T effector cell clonal expansion against EBV in APOE4 carriers. These
results indicate that antigen-experienced T cells patrol the intrathecal space of brains affected by AD in an APOE
allele-specific manner. We hypothesize that CD8 T cells patrol the blood and CSF of APOE4 AD patients and
contribute to neuroinflammation via aberrant anti-viral antigen control. Specific Aim 1 will utilize single cell RNA
sequencing (scRNAseq) and immunohistochemistry to determine the influence of APOE alleles on adaptive
immunity in the AD brain. Specific Aim 2 will use high throughput scRNAseq to assess B and T cell clonal
expansion in peripheral blood of various APOE carriers combined with sophisticated bioinformatic approaches
to compare the transcriptomes of anti-viral adaptive immune cells in an APOE allele-dependent manner.
Specific Aim 3 will employ ApoE structure correctors and CRISPR gene editing to determine the mechanistic
impact of ApoE on the anti-viral immune response and T cell killing of neurons. These studies will be conducted
in the lab of Dr. David Gate, an early-stage investigator who has extensive experience studying T cells, anti-viral
immunity and neurodegeneration. Collaborators include Dr. Robert Mahley (Gladstone Institute), who has
expertise in ApoE biology, Dr. Robert Vassar (Northwestern University), who has expertise in AD pathobiology,
and Dr. Marsel Mesulam, who will provide access to patient specimens through the Northwestern Mesulam
Center for Cognitive Neurology and Alzheimer's Disease.

## Key facts

- **NIH application ID:** 10674878
- **Project number:** 5R01AG078713-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** David Gate
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $607,408
- **Award type:** 5
- **Project period:** 2022-08-02 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10674878

## Citation

> US National Institutes of Health, RePORTER application 10674878, The role of apolipoprotein E in Alzheimer's adaptive immunity (5R01AG078713-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10674878. Licensed CC0.

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