# Resolving selective vulnerability and disease progression in human Alzheimer's brain via single-cell RNA-seq

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $391,250

## Abstract

ABSTRACT
Effective therapies for Alzheimer’s disease (AD) are urgently needed. The existing approaches have largely
failed to improve symptoms or modify disease progression, in part because of our incomplete understanding of
the disease pathogenesis. Previous neuropathology and neuroimaging studies have been instrumental in
establishing the histopathological hallmarks of AD and the involvement of specific brain regions. However, the
selective vulnerability of distinct neuronal and non-neuronal cell types to AD and the underlying molecular
mechanisms remain largely unknown. We hypothesize that subpopulations of neuronal and non-neuronal cell
types contribute distinctively to AD and propose the use of single-cell transcriptomics in human brain to identify
these cell types and the underlying molecular mechanisms leading to AD pathology. Although applying this
innovative technology to human brain is challenging, human AD brain is crucial for understanding the
contributions of distinct cell types to disease, identifying the earliest pathogenic events, uncovering
neuroprotective pathways, and defining the spread of pathology. We will study early- and late-affected cerebral
cortical regions, including entorhinal, association, and primary sensory cortices, from subjects encompassing
the full spectrum of disease progression (Braak stages I–VI) and age-matched healthy controls. This strategy
will provide a comprehensive landscape of the vulnerable and resilient cell types, their transcriptome changes,
and the spread of changes over time and across cortical regions. In Aim 1 we will use single-nucleus RNA-
sequencing for the unbiased identification and transcriptome profiling of neurons, glia (microglia, astrocytes, and
oligodendrocytes), and blood vessel cells. In Aim 2 we will test the hypothesis that distinct molecularly defined
subpopulations of cortico-cortical and cortico-thalamic projection neurons are selectively vulnerable to
degeneration. In Aim 3 we will examine the molecular changes associated with tau pathology using our newly
developed assay for purifying and profiling single neurons bearing neurofibrillary tangles. These studies will
generate the first single-cell transcriptome profiling of human neurons with tangles and provide insight into the
tau-mediated mechanisms of neurodegeneration. Together, our studies will provide an unbiased and robust
identification of the vulnerable and resilient cell types in AD and insight into the molecular mechanisms underlying
the selective vulnerabilities. These data will provide a valuable resource to the scientific community for improved
cell-type-based disease modeling and drug discovery.

## Key facts

- **NIH application ID:** 10407487
- **Project number:** 5R01AG059848-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Inma Cobos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407487

## Citation

> US National Institutes of Health, RePORTER application 10407487, Resolving selective vulnerability and disease progression in human Alzheimer's brain via single-cell RNA-seq (5R01AG059848-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10407487. Licensed CC0.

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