# Multi-omic Brain Cell Atlas of Alzheimer's Disease Progression

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $1,923,515

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD) is the most common form of dementia in the elderly, affecting more than 5 million
Americans, as well as their families and caregivers. Unfortunately, aging of the global population is only
worsening the AD “epidemic”, as incidence is projected to triple by 2050. Despite intense research, there is
currently no cure for this devastating neurodegenerative disorder. Thus, understanding the intrinsic molecular
mechanisms that drive AD pathology and progression is critical to devising effective treatments. Postmortem
examination of human brains has revealed that AD-associated neuropathologies, such as neurofibrillary tangles
(NFTs) and neurodegeneration, generally arise in a conserved spatio-temporal pattern, affecting transentorhinal
regions first, and later extending to limbic and isocortical areas. The molecular and neurochemical bases for
such selective neuronal vulnerability (SNV) have long been pursued, as they underlie disease progression and
may hold the key to understanding the molecular underpinnings of neurodegeneration, but to date these
mechanisms remain elusive. Here, cutting-edge, single-cell technologies will be used to generate a
comprehensive, multi-omic atlas of cell types within AD-vulnerable brain regions across different stages of
disease. The hypothesis is that specific cell types most dramatically affected by AD pathology within susceptible
brain regions are characterized by distinct molecular pathways (transcription factors, signaling cascades, gene
networks) that drive SNV. Moreover, that these pathways are executed in a sequential spatio-temporal pattern
by changes in chromatin architecture and gene regulatory elements. Tracking the molecular changes exhibited
by these neuronal cell populations in the continuum of AD pathology will better define AD onset and progression,
and potentially indicate new therapeutic targets. Postmortem brain samples will be obtained from healthy
controls, or patients who at death exhibited different stages of AD pathology, namely early (Braak III/IV), or late
(Braak V/VI). Changes occurring at different stages of AD progression will be analyzed to identify the cell types
and molecular pathways most critical for the initiation and spread of AD-related pathology. Regions analyzed will
be hippocampus (CA1/sub), inferior temporal cortex (BA20), frontal cortex (BA9), and visual cortex (an AD-
resistant region). In Aim 1, samples from control subject will be subjected to single cell analyses to characterize
the methylome and chromatin architecture jointly (sn-m3C-seq), as well as chromatin accessibility together with
transcriptome (Paired-seq), of cell types within AD-vulnerable brain regions. Integration of these datasets will
create a multi-omic atlas of relevant cell types that will serve as the foundation for understanding AD onset and
progression. In Aim 2, these analyses will be extended to AD patients. Comparing data sets across brain regions
and ...

## Key facts

- **NIH application ID:** 10461533
- **Project number:** 7R56AG069107-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** BRADLEY T. HYMAN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,923,515
- **Award type:** 7
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461533

## Citation

> US National Institutes of Health, RePORTER application 10461533, Multi-omic Brain Cell Atlas of Alzheimer's Disease Progression (7R56AG069107-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10461533. Licensed CC0.

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