# The Enhancer Code of AD-A Genetic Approach

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $1,063,676

## Abstract

Project Summary
Genetic and genome wide association studies (GWAS) have identified numerous genes and risk alleles that
indicate both cell autonomous and non-cell autonomous mechanisms contributing to Alzheimer's Disease
(AD). In addition to genes expressed by neurons, the observation that several risk alleles, such as TREM2,
are exclusively or mainly expressed in microglia, has led to increased efforts to understand the roles of
microglia in AD pathology. Importantly, the majority of risk variants identified by GWAS reside in non-coding
regions of the genome, implying that some act to alter gene expression. Our recent comparisons of neurons
derived by trans-differentiation of fibroblasts from AD subjects and age matched controls demonstrate marked
changes in gene expression in AD neurons. In parallel, our recent ability to globally analyze the
transcriptomes and enhancer atlases of human microglia demonstrated marked individual variation in
expression of immune genes associated with AD risk alleles. Collectively, these findings suggest widespread
alterations in the expression of genes that may contribute to susceptibility of AD independent of the generation
of βamyloid. Enhancers have emerged as major points of integration of intra and extra-cellular signals
associated with development, homeostasis and disease, resulting in context-specific transcriptional outputs.
By defining a cell's enhancer landscape, it is possible to both infer the environmental signals the cell is
receiving and explain its consequent program of gene expression. In this application, we propose to define the
`Enhancer codes of Alzheimer's Disease' to qualitatively advance our understanding of cell autonomous and
non-cell autonomous factors that drive pathogenic programs of gene expression. In Specific Aim 1, we will
define transcriptomes and enhancer landscapes of nuclei isolated from neurons and microglia derived from
sporadic and genetic AD brains and brains from age and sex-matched controls. These studies will enable an
unprecedented analysis of the regulatory landscapes of neurons and microglia in the intact aging and AD
brain. In Specific Aim 2, we will validate and explain AD-specific enhancer codes of neurons by direct
reprogramming of fibroblasts from sporadic and genetic AD patients and age/sex-matched control subjects. In
Specific aim 3, we will define cell autonomous AD-specific enhancer codes of microglia obtained by
reprograming of iPSCs and monocytes from control and AD subjects. These studies will build upon our recent
characterization of human microglia transcriptomes and enhancer landscapes that demonstrate striking levels
of individual variation in the expression of genes linked to risk of AD. In Specific Aim 4, we will define
consequences of neuron-microglia interactions on the transcriptomes and epigenomes of each cell type. By
leveraging existing resources and data sets, these studies will define transcriptional networks that are
dysregulated in neurons...

## Key facts

- **NIH application ID:** 10399455
- **Project number:** 5R01AG056511-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christopher K Glass
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,063,676
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399455

## Citation

> US National Institutes of Health, RePORTER application 10399455, The Enhancer Code of AD-A Genetic Approach (5R01AG056511-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399455. Licensed CC0.

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