# Project 4: Cross-species Dissection of Cellular Response to APOE Genotype and AD Pathology Using Single-cell Multi-omics

> **NIH NIH P01** · J. DAVID GLADSTONE INSTITUTES · 2021 · $965,724

## Abstract

PROJECT 4 – SUMMARY
Alzheimer’s disease (AD) is driven by a complex, multifactorial etiology that has stymied progress toward
effective therapies. Despite decades of research on amyloid-beta (Aβ) and tau, we do not fully understand the
cellular and molecular effects of these key disease drivers. These pathologic proteins interact with genetic
drivers, such as apolipoprotein E4 (APOE4), creating complex and diverse cellular and brain-regional effects.
One promising approach to understanding the diverse effectors of AD pathogenesis is to study central processes
that are perturbed by each disease driver. Both AD pathology and APOE genotype exacerbate neural network
dysfunction in brain regions critical for cognition, nominating neural network function as one such critical central
process. Besides causing AD-related cognitive decline, neural network dysfunction results in comorbidities such
as subclinical epileptiform activity. The lack of a comprehensive picture of the cellular, molecular, and genetic
underpinnings of AD underscores the need for detailed and rigorous dissection of the many factors that contribute
to this disease. The goal of this PPG is to identify the cellular and molecular consequences of the interactions
between Aβ, tau, and APOE and determine how they lead to prolonged neural network dysfunction.
 Genetic and pathologic alterations drive AD by affecting cellular state. For example, neuronal and glial cells
interact with and are affected by Aβ and tau pathology, leading to changes in gene expression that are further
altered by the genetic milieu of the cell, culminating in an altered cellular state. Understanding how cellular state
changes and is controlled by multifactorial inputs of AD could lead to novel therapeutic strategies. However,
these cellular responses are cell type– and cell context–specific. Techniques for single-cell transcriptomic and
epigenomic profiling now make it possible to characterize the specific cellular response to combinatorial
interactions between Aβ, tau, and APOE. To systematically understand cellular responses to Aβ, tau, and APOE
in human AD, Project 4 will comprehensively characterize cell-type-specific transcriptomics and epigenomics in
primary human samples.
 In Aim 1, we will perform single-nucleus (sn) transcriptomic and epigenomic profiling in human cohorts that
have been rigorously characterized, both clinically and pathologically, and that vary in APOE genotype, Aβ and
tau pathology, and cognitive state. In Aim 2, we will integrate these data with snRNA-seq results from novel
humanized mouse lines designed to dissect the combinatorial effects of Aβ, tau, and APOE (with Projects 1–3).
In Aim 3, we will use single-cell technologies to understand the effects of therapeutic reversal of prolonged neural
network dysfunction in mouse models (with Projects 2 and 3). The results of the proposed studies, in concert
with the other complementary projects, will provide an unparalleled characterization o...

## Key facts

- **NIH application ID:** 10271129
- **Project number:** 1P01AG073082-01
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Michael Ryan Corces
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $965,724
- **Award type:** 1
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271129

## Citation

> US National Institutes of Health, RePORTER application 10271129, Project 4: Cross-species Dissection of Cellular Response to APOE Genotype and AD Pathology Using Single-cell Multi-omics (1P01AG073082-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10271129. Licensed CC0.

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