# Discovery and validation of genetic variants affecting microglial activation in Alzheimer's disease

> **NIH NIH RF1** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $6,213,164

## Abstract

Project Summary/Abstract. While activated microglia have been observed in the vicinity of neuritic amyloid
plaques in Alzheimer's disease (AD), there have been no large-scale assessments of microglial activation in
aging and neurodegenerative disease. Our long-term goal is to understand the genetic underpinning of microglial
responses—particularly the proportion of microglia in a morphologically-defined state of activation—that increase
susceptibility to AD, so we can develop more targeted forms of immune-based therapies to prevent cognitive
decline and progression to dementia. Our objective is to refine the genetic architecture of microglial activation to
identify novel loci that influence the proportion of activated microglia, and to understand the functional
consequences of variants driving microglial activation in AD. Our central hypothesis is that identifiable gene
variants influence microglial activation and susceptibility to AD. We will test this hypothesis by conducting
genome-wide analysis and identifying associations between gene variants and microglial activation. Microglial
activation will be measured in human autopsy tissue (ex vivo), living human brain using PET imaging (in vivo),
and in monocyte-derived microglia-like cells (in situ and in vitro). Our rationale is that mapping the genetic
architecture that drives the proportion of activated microglia will be important in developing a first generation of
polygenic models for this trait and determine whether the proportion of activated microglia captures a causal
element of the cascade leading to AD. Our specific aims are 1) Validation and discovery of loci influencing a
postmortem measure of human microglial activation (proportion of activated microglia) in aging and Alzheimer's
disease, 2) In vivo validation of GWAS and assessment of clinical relevance using TSPO PET imaging to
measure microglial activation, and 3) In situ histological and in vitro functional characterization of validated
variants in a human microglia-like system. For the first aim, we will perform GWAS and measure the proportion
of activated microglia in autopsy brain tissue from 1,600 individuals, and then replicate our findings in an
independent, diverse set of samples from three separate institutions. In the second aim, we will perform GWAS
and TSPO PET imaging, using the state-of-the-art radioligand 11C-ER176, in a prospective cohort of 200 older
human subjects (equal proportions of cognitively normal, mild cognitive impairment, and Alzheimer's disease) to
identify gene variants associated with AD-related microglial activation. In the third aim, we will assess how gene
variants identified in Aims 1 and 2 influence cellular function and protein expression in monocyte-derived
microglia-like cells. Our innovative approach combines autopsy, PET, and human cell measures of microglial
activation to create a multimodal investigation into the genetic architecture of microglial responses. The proposed
research is signi...

## Key facts

- **NIH application ID:** 10101207
- **Project number:** 1RF1AG070438-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** PHILIP L DE JAGER
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $6,213,164
- **Award type:** 1
- **Project period:** 2020-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101207

## Citation

> US National Institutes of Health, RePORTER application 10101207, Discovery and validation of genetic variants affecting microglial activation in Alzheimer's disease (1RF1AG070438-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10101207. Licensed CC0.

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