# Studying the impact of altered CD8+ T cell immunity in Alzheimer's disease

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $418,750

## Abstract

Project Summary. Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder that
accounts for 60-70% of all cases of dementia. Genetic studies reported the possible causative role of amyloid-
β (Aβ), which is derived from the amyloid precursor protein (APP), in the development of AD. The
accumulation of Aβ peptides in the brain can initiate the pathophysiology of AD, leading to neurofibrillary
tangles and neurodegeneration. Preclinical and postmortem studies demonstrate a significant association
between inflammatory pathways and the development of AD pathology. However, previous studies have
focused mostly on innate immune cells. Alterations in the immune system, including T cells, occur with aging,
likely contributing to the development of infections and malignancies. In human T cells, probably the most
prominent change with aging is memory CD8+ T cell expansion in peripheral blood although alterations in CD4+
T cell subsets are reported as well. We found the age-associated expansion of human effector memory (EM,
CCR7-CD45RA+/-) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) which have distinct
characteristics including effector molecules, transcription factors, and DNA methylation profiles. Recently, we
investigated the possible relationship of this age-associated expansion of IL-7Rαlow EM CD8+ T cells with the
global transcriptomic profile of peripheral blood cells in humans. Crossing differentially expressed genes
(DEGs) in IL-7Rαlow EM CD8+ T cells against age-associated genes from human peripheral blood revealed an
age-associated gene expression signature of the IL-7Rαlow EM CD8+ T cells that corresponded to 15% of the
age-associated genes (244/1,497) reported by a meta-analysis study on human peripheral whole blood from
approximately 15,000 individuals. A recent study reported the expansion of CD45RA+ EM CD8+ T cells in
peripheral blood and cerebrospinal fluids of patients with dementia or mild cognitive impairment (MCI) due to
AD, correlating with cognition. Importantly, such cells are mostly IL-7Rα(CD127)low cells. Thus, we will
investigate the possible implication of the age-associated expansion of IL-7Rαlow cells in AD based on the
hypothesis that patients with AD have increased levels of IL-7Rαlow EM CD8+ T cell gene signature and an
expansion of these cells in peripheral blood, correlating with measures of AD severity and brain synaptic
density. The goal of the proposal is to test the hypothesis with the following aims: 1) Aim 1. Elucidate that
patients with AD have increased levels of IL-7Rαlow EM CD8+ T cell gene signature in peripheral blood which
correlate with disease severity and brain synaptic density; and 2) Aim 2. Elucidate that patients with AD have
an altered T cell profile correlating with disease severity and brain synaptic density. Overall, our supplement
proposal is unique and significant since it conducts in-depth studies on the role of CD8+ T cells, especially IL-
7Rαlow EM ce...

## Key facts

- **NIH application ID:** 10119925
- **Project number:** 3R01AG056728-03S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Insoo Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 3
- **Project period:** 2018-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119925

## Citation

> US National Institutes of Health, RePORTER application 10119925, Studying the impact of altered CD8+ T cell immunity in Alzheimer's disease (3R01AG056728-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10119925. Licensed CC0.

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