# Single-cell epigenomic roadmap of Alzheimer's disease

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $41,862

## Abstract

Project Summary/Abstract
Genetic variation drives phenotypic variation across many traits, including heritable risk for disease
susceptibility in neurodegenerative disorders such as Alzheimer’s Disease (AD). For complex polygenic human
diseases, it is difficult to unravel precisely which molecular changes are brought on by genetic risk factors. It is
well known that genetic variants at the APOE locus can confer a neuroprotective status from AD, while another
variant drastically increases one’s chances of developing disease. Even these well studied variants are not
fully understood at the molecular level. The majority of disease-associated risk variants for AD and other
disorders lie in non-coding regulatory elements and are therefore best studied using epigenomic techniques.
Since previous studies have shown that AD affects different brain regions and cell types throughout its
progression, I hypothesize that the mechanisms underlying genetic risk for AD act similarly in a progressive,
region-specific, and cell-type-specific manner. In this proposal, we aim to generate chromatin accessibility
profiles for single cells across the prefrontal cortex, the hippocampus, and the entorhinal cortex of AD patient
brains, and integrate with published single cell transcriptomics data, thereby allowing us to identify enhancer-
gene interactions that are disrupted by AD risk variants. Our preliminary work has shown that microglia-specific
enhancers are enriched for AD genetic risk factors. Therefore, we will use CRISPR-cas9 to delete an enhancer
linked to the variant rs4663105 at the BIN1 locus in induced pluripotent stem cell (iPSC) derived microglia,
thereby allowing us to unravel its role in the regulatory landscape. My preliminary data from the prefrontal
cortex shows that the chromatin accessibility landscape is highly cell-type specific and is significantly altered in
AD patient brains, and I expect that we will find regional specificity of regulatory elements that are disrupted by
AD risk variants. Aside from our specific task of identifying these disease-associated regulatory elements, an
integrated study of single-cell epigenomics and single-cell transcriptomics data in AD brains will be of great
value to the broader AD community to further implicate genes, networks, and pathways as targets for future
studies.

## Key facts

- **NIH application ID:** 10390136
- **Project number:** 1F31AG076308-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Samuel Joseph Morabito
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,862
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390136

## Citation

> US National Institutes of Health, RePORTER application 10390136, Single-cell epigenomic roadmap of Alzheimer's disease (1F31AG076308-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10390136. Licensed CC0.

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