# Interrogation of a human microglia phenotype associated with Alzheimer's disease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $369,470

## Abstract

PROJECT SUMMARY/ABSTRACT
Study rationale. Microglia, the resident innate immune cells of the central nervous system, are involved in the
maintenance of tissue homeostasis and neuronal circuitry. These microglia specific processes are believed to
become dysregulated during neurodegenerative diseases, such Alzheimer’s disease (AD). It has also been
shown that many of the AD susceptibility genes are primarily expressed in microglia in the brain. Given these
observations, it has been suggested that microglia would constitute an ideal point of intervention for future
preventive and disease modifying therapies for AD. Nonetheless, the notion arose, that such a plastic and
reactive cell type as the microglia would not exist in a single state in such a complex and diverse environment
as the aging brain. This also implies the possibility, that the different subsets would be involved in different
aspects of physiological and pathological processes. Indeed, in our recent single cell RNA sequencing study
we have identified several distinct microglia subpopulations in the aged human brain, that showed (in an
indirect analysis) divergent associations with clinical and histopathological characteristics of brain aging and
AD. Intriguingly, the signature of one particular microglia subset, named Cluster 7, showed an inverse
relationship with both tau pathology and clinical AD, suggesting a potential protective role for this microglia
phenotype. Thus, the overarching goal of the proposed project is to explore the identity of Cluster 7 microglia
and to understand how sex, aging, AD pathology and genetics influence its abundance in the human brain. Our
hypothesis is that aging, AD pathology and genetic susceptibility converge on microglia and result in a
differentiation deficit in particular towards the beneficial Cluster 7 phenotype, thus contributing to disease
progression. We also hypothesize that this process is more pronounced in females than in males. Accordingly,
the objective of the current proposal is: 1) to investigate how the abundance of this phenotype relates to
histopathological and clinical features of brain aging and AD; 2) to understand what are the factors that might
inhibit Cluster 7 microglial fate choice in AD; 3) to explore whether elevated Cluster 7 abundance is associated
with cognitive resilience; and 3) to describe the phenotypic characteristics and epigenetic regulatory landscape
of Cluster 7 microglia. These goals will be achieved through the following 3 aims: In Aim 1 we propose to
measure in situ the abundance of Cluster 7 microglia subpopulation in a large number of aged individuals with
and without AD dementia and will establish the relationship between the abundance of Cluster 7 and sex, age,
histopathological features, AD endophenotypes, AD susceptibility alleles and measures of cognition. In Aim 2,
we will explore the functional and phenotypic characteristics of ex vivo isolated Cluster 7 microglia. In Aim 3,
we will investigate th...

## Key facts

- **NIH application ID:** 10884107
- **Project number:** 4R01AG072471-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Marta Olah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $369,470
- **Award type:** 4N
- **Project period:** 2021-04-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884107

## Citation

> US National Institutes of Health, RePORTER application 10884107, Interrogation of a human microglia phenotype associated with Alzheimer's disease (4R01AG072471-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10884107. Licensed CC0.

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