# Dynamic immune cell landscape in late-onset Alzheimer's disease: role of ApoE-mediated microglial lipid metabolism

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $451,042

## Abstract

Project Summary
Alzheimer's disease (AD) is the leading cause of dementia in older adults and affects over 5 million individuals
in the United States alone. The more common form of AD, late-onset, is a multifactorial disorder in which ApoE4
is the most potent genetic risk. The ApoE4 isoform is also linked to midlife obesity which can cause cognitive
decline in older adults. Obesity is a condition of chronic inflammation characterized by activated immune cells
and increased inflammatory mediators in the blood. Recently, through genetic association studies, microglia and
other myeloid origin immune cells have emerged as crucial players in AD pathogenesis. Single-cell RNA
sequencing analysis in mouse and human AD brains has identified a distinct subset associated with amyloid
plaques and the upregulation of ApoE in microglia. Therefore, further investigation of microglia and other immune
cells is needed to understand how these cells are affected by ApoE4 isoform and obesity contributing to late-
onset AD progression. Our objective in this R21 project is to explore the gene-environment interactions between
ApoE4 and obesity in regulating phenotypic plasticity of microglia and peripheral immune cells. This project aims
to identify molecular pathways that could restore healthy immune function to treat late-onset AD. Our Specific
Aims are to (1) Assess dynamic changes of brain immune cell populations influenced by ApoE4 and diet-induced
obesity in human ApoE isoform knock-in mice; (2) Identify altered lipid metabolism in ApoE4 microglia that
modulates the phenotypic plasticity. The successful completion of this project will reveal the multifaceted roles
of ApoE4 in modulating immunometabolism. Moreover, it will provide a strong rationale for lifestyle interventions
or individualized therapeutic strategies for late-onset AD in ApoE4 carriers.

## Key facts

- **NIH application ID:** 10370588
- **Project number:** 1R21AG070971-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** I-Chen Ivorine Yu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $451,042
- **Award type:** 1
- **Project period:** 2022-03-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370588

## Citation

> US National Institutes of Health, RePORTER application 10370588, Dynamic immune cell landscape in late-onset Alzheimer's disease: role of ApoE-mediated microglial lipid metabolism (1R21AG070971-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10370588. Licensed CC0.

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