# Topographic, cell type and molecular pathway characterization ofAlzheimer's disease using single cell transcriptomics and epigenomics

> **NIH NIH U19** · ALLEN INSTITUTE · 2020 · $3,757,393

## Abstract

ABSTRACT (PROJECT 2)
 Alzheimer's disease (AD) is a highly penetrant neurodegenerative disease projected to affect 13.8 million
cases in the US by 2050 at a cost of $1.1 trillion if no treatment is developed. AD is characterized by stereotyped
progressive neurodegeneration and accumulation of two misfolded proteins in brain regions important for
cognition and memory. Neurofibrillary tangles (NFTs) of hyperphosphorylated tau follow a progression like
neurodegeneration, while extracellular amyloid beta (Aβ) plaques are initially detected in cortical and deep brain
structures. It is unclear whether these pathologies are causal or effects of other underlying processes and
currently no anti-tau or anti- Aβ therapies stop or reverse AD. Gene expression studies of AD have largely been
performed on tissue or cell populations, and impact of neuronal loss and gliosis on these results is unknown.
Epigenetic modifications are also associated with AD, though methylation studies have produced conflicting
results and no clear pattern of epigenetic dysregulation associated directly with AD progression has emerged.
 The present study adapts recently developed high-throughput, single-cell methods for transcriptomic and
epigenetic analysis to the identify molecular and gene regulatory hallmarks of “clinically typical” AD without
significant co-morbidities. Building off a detailed understanding of neurotypical adult cell types, the project aims
to identify transcriptional changes in specific cell types or classes correlated with increasing severity of AD
pathology in different brain regions affected by the disease, and then identify gene and chromatin accessibility
changes with pathology in vulnerable cell populations. This project will initially optimize single nucleus RNA-seq
and epigenetics methods for use with postmortem samples of varying pathology and tissue quality, and generate
reference datasets for brain regions to be analyzed in AD. Low-cost, droplet-based single nucleus RNA-seq will
then be used to classify and characterize cell types in regions differentially affected by tau and amyloid pathology
from many donors spanning AD progression with quantified tau and Aβ pathologies. A broader set of brain
regions will then be surveyed on a subset of cases with consistent AD-related phenotypes to understand whether
there is a common AD signature across brain regions, and whether signatures of AD can be detected prior to
the emergence of neuropathology. Finally, higher-resolution methods will target transcriptomic and epigenetic
changes in AD associated with pathology and disease diagnosis in specific cell types, aimed at achieving a
mechanistic understanding of AD phenotypes. Using this design, this project can directly probe dysregulated
gene networks within affected cell types for the first time, providing a potential causal link between genetic or
epigenetic states and resulting gene expression. The resulting datasets and platform will produce valuable
insig...

## Key facts

- **NIH application ID:** 9855877
- **Project number:** 1U19AG060909-01A1
- **Recipient organization:** ALLEN INSTITUTE
- **Principal Investigator:** Ed Lein
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,757,393
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855877

## Citation

> US National Institutes of Health, RePORTER application 9855877, Topographic, cell type and molecular pathway characterization ofAlzheimer's disease using single cell transcriptomics and epigenomics (1U19AG060909-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9855877. Licensed CC0.

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