# Single-cell Epigenome Analysis of the Alzheimer's Disease Brain

> **NIH NIH R43** · EPIGENOME TECHNOLOGIES, INC. · 2022 · $499,475

## Abstract

Title: Single-cell Epigenome Analysis of the Alzheimer’s Disease Brain (PI: Hartl)
 Alzheimer’s disease (AD) affects more than 6 million American but no cures and few effective treatments
are available. Genome-wide association studies (GWAS) have uncovered thousands of segregating mutations
that significantly increase AD risk. Most of these variants alter non-protein-coding sequence and lack clear
functional annotation, hindering efforts to translate risk-conferring mutations into curative or preventative
therapies. Heritability partitioning suggests that these variants likely perturb gene expression in glial cells
(especially microglia), ultimately leading to AD pathology. Linking these variants – and their downstream effects
– to specific regulatory networks and pathways has been hindered by a lack of cis-regulatory element maps for
these major glial cell classes and their subtypes. The proposed study addresses this critical knowledge gap by
applying a cutting-edge single cell multi-omic technology to postmortem human brain samples from
phenotypically normal donors and AD patients. Specifically, the chromatin accessibility or histone modifications
will be interrogated jointly with gene expression at single cell resolution in dorsolateral prefrontal cortex (DLPFC)
from multiple donors, to identify and characterize the cell-type-specific gene regulatory elements that drive
aberrant cell states and disease-relevant cellular responses in human AD brains. The single cell chromatin state
and gene expression atlases from phenotypically normal individuals will be compared to those from AD subjects
to determine the brain cell types, genes and regulatory elements that exhibit significant changes in pathological
conditions. Finally, the newly generated cell-type resolved epigenome maps will be integrated with public
genomic resources to provide functional annotation of the AD risk variants, identify disease-relevant cell types,
prioritize genes, transcription factors, and molecular pathways for future mechanistic investigation. Results of
the proposed study will provide a much-needed tool for study of AD pathogenesis and development of improved
AD therapies.

## Key facts

- **NIH application ID:** 10546522
- **Project number:** 1R43AG079691-01
- **Recipient organization:** EPIGENOME TECHNOLOGIES, INC.
- **Principal Investigator:** Christopher Hartl
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $499,475
- **Award type:** 1
- **Project period:** 2022-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546522

## Citation

> US National Institutes of Health, RePORTER application 10546522, Single-cell Epigenome Analysis of the Alzheimer's Disease Brain (1R43AG079691-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10546522. Licensed CC0.

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