# The impact of Alzheimer's disease susceptibility alleles on microglia transcriptome

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $466,125

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive
decline and dementia. Although the mechanisms underlying AD are still largely unknown, it is clear that aging
of the brain is a key risk factor for this disease. Several lines of evidence indicate that microglia, the myeloid
immune cells of the brain, play a crucial role in the processes involved in normal aging of the central nervous
system and development of AD. Recent genetic studies have identified over twenty novel AD risk loci, and
network analysis have shown that a major part of these loci play a role in the myeloid immune system. In
addition, gene expression changes have been found in microglia of aged individuals, subjects with AD and in
microglia in mice models for AD. How these microglia changes contribute to AD is not yet clear. Answering this
question is an important step towards understanding the mechanisms involved in AD. In addition, this could
lead to unravelling novel targets for treatment of AD and related neurodegenerative disorders. The long-term
goal of this project is to deepen our insight into the role of microglia cells in AD and to identify microglia-related
targets for treatment of age-related disorders of the central nervous system. An important first step towards
reaching this goal is to understand what the changes that have been found microglia in AD tell us in terms of
changes in gene and protein expression and functions. The overall objective of this study is therefore to
identify the AD-associated common genetic variants that alters microglia gene expression at baseline and in
response to inflammatory stimuli. By combining the unique expertise of the two PIs in the isolation and culture
of human microglia, as well as advanced computational genomics analysis of human myeloid immune cells. In
Aim 1, we will use 264 existing microglia samples that we have previously isolated of different regions of 103
brain donors to generate genotype and transcriptome profiles. By combining these data with existing microglia
transcriptomic datasets, we will be able to generate a map of how AD-associated genetic loci influence gene
expression (or expression quantitative trait loci, eQTL) and splicing (sQTL). In aim 2, we will use interferon
(IFN) stimulated microglial samples that we have previously collected to characterize how AD-associated risk
variants alter IFN-stimulated transcriptome changes. These profiles will be validated in new microglia
transcriptomes from an independent cohort of 15 donors to determine the response of these samples to
interferon and Aβ and sort subsets with different phagocytic capacity. The transcriptome profiles and
expression and splicing QTL that will be generated in these two aims will be made publically available and we
will apply these profiles to very large available gene datasets on aged and AD brain tissue and peripheral
monocytes to investigate how gene expression change...

## Key facts

- **NIH application ID:** 9896409
- **Project number:** 1R21AG063130-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Towfique Raj
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,125
- **Award type:** 1
- **Project period:** 2020-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896409

## Citation

> US National Institutes of Health, RePORTER application 9896409, The impact of Alzheimer's disease susceptibility alleles on microglia transcriptome (1R21AG063130-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896409. Licensed CC0.

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