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

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $133,227

## Abstract

Abstract
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. 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. In this administrative supplement, we plan to sequence an additional 82
microglial samples that we have isolated and stored. This would increase the number of samples in our study to
343, which is much greater than any of the studies currently published. 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 changes relate to changes in microglia function. Together, we expect that this
study will provide key information bridging AD genetics to molecular mechanisms i...

## Key facts

- **NIH application ID:** 10162110
- **Project number:** 3R21AG063130-01A1S1
- **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:** $133,227
- **Award type:** 3
- **Project period:** 2020-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162110

## Citation

> US National Institutes of Health, RePORTER application 10162110, The impact of Alzheimer's disease susceptibility alleles on microglia transcriptome (3R21AG063130-01A1S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10162110. Licensed CC0.

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