# Peripheral Adaptive Immune System Changes Associated with Alzhiemer's Disease

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2021 · $433,126

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer disease (AD) is the most common form of age-related cognitive failure in humans. Progressive
accumulation of b-amyloid (Ab) and neuroinflammation of certain parts of the brain are dominant pathological
features of AD 1. Aging represents the greatest risk for development of AD. As like in the brain, aging in humans
is associated with many changes in the peripheral adaptive immunity. Most of the genetic association in AD
points to genes involved in innate inflammation and microglial cell activation, adaptive immunity and its role in
cognitive decline and AD is almost ignored. However, the presence of Ab specific T cells has been noted in AD
patients and shown to increase with age. Recently, by employing unbiased approaches we explored the role of
T cells in multiple cohorts of AD patients as well as age and sex matched healthy controls. Our study showed
that there is increased frequency of effector memory CD8 T cells in the peripheral blood and cerebrospinal fluid
of AD patients with enhanced proinflammatory potential. In addition, we found that these CD8 effector T cells
were negatively correlated with cognition. Further, T cell receptor (TCR) sequencing in the peripheral blood and
cerebrospinal fluid showed increased clonal expansion. Our study also associated a T cell immune signature
with higher clonal expansion in AD. However, whether these T cells are beneficial or detrimental in AD, whether
these clonal T cells respond specifically to Ab, and what their actual TCR repertoire and phenotypes are in AD
remain unknown. Therefore, additional studies are required to gain insight into the role of CD4 and CD8 T cell
reactivity to Ab in AD. With increasing evidence for T cell effects in AD, our central hypothesis is that the
dysregulated amyloid specific T cell responses contribute to AD pathogenesis. We will address this hypothesis
by determining 1) the Ab specific T cell responses in healthy controls and AD patients and 2) the Ab specific T
cell receptor (TCR) repertoire in healthy controls and AD patients. The proposed studies will lay the groundwork
to enhance our understanding of Ab mediated T cell response and unique cellular and molecular programming
pathways. Further, testing intrinsic CD4 and CD8 T cell activity in AD patients to Ab before offering Ab-based
immunotherapy based in AD will help stratify patients and have major implications for future Ab-directed
therapies.

## Key facts

- **NIH application ID:** 10194864
- **Project number:** 1R21AG072155-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Naresha Saligrama
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $433,126
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194864

## Citation

> US National Institutes of Health, RePORTER application 10194864, Peripheral Adaptive Immune System Changes Associated with Alzhiemer's Disease (1R21AG072155-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10194864. Licensed CC0.

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