# Human Ear Cellular Atlas

> **NIH NIH U24** · STANFORD UNIVERSITY · 2024 · $386,000

## Abstract

Molecular markers of Alzheimer’s disease pathology in the human inner ear (NOT-AG-23-032)
ABSTRACT
Alzheimer’s disease (AD) is the most common cause of dementia in the United States and, in addition to the
classical symptoms such as memory loss, people with AD have abnormal perceptual and semantic processing
of sound. As hearing loss has recently been identified as one of the top risk factors for the development of
dementia, there is an urgent unmet need to identify the etiological link between hearing loss and AD, and to
develop early interventions. Specifically, the hallmark AD pathology causing neurodegeneration in the brain—
the deposition of amyloid-beta (Aβ) protein and phosphorylated tau (p-tau) tangles in the brain— may similarly
cause cellular toxicity at the level of the cochlea, damaging the fragile, non-regenerating sensory cells required
for human hearing.
We propose to test this hypothesis via the expansion of Aim 2 of our grant, “Human Ear Cellular Atlas,” and
conduct a multi-faceted analysis of AD pathology in the human inner ear. In Aim 2i, we will define the proteomic
signature of perilymph rapidly collected from patients with AD postmortem, and identify proteins unique to or
differentially expressed in AD patient perilymph compared with that from age-matched, cognitively normal
controls. In Aim 2ii, we will use the collected temporal bones of AD patients to quantify cochlear hair cells,
spiral ganglion neurons (which transmit auditory information to the brain), and synapse density between hair
cells and SGNs, to determine if pathological changes occur within the AD cochlea compared with controls.
Additionally, we will examine the expression of 100+ proteins (identified from perilymph in Aim 2i and including
AD-associated proteins) using a highly multiplex approach along with single-cell imaging. Lastly, in Aim 2iii, we
will correlate AD patients’ perilymph proteomic signatures and cochlear pathology from Aims 2i and 2ii,
respectively, with their clinical and hearing data contained in electronic medical records. We will analyze AD
patients’ (1) level of hearing impairment, including audiometric thresholds, word recognition score, and speech-
in-noise score; (2) cortical load of p-tau and Aβ measured by clinical imaging or from brain sections; and (3)
results of cerebrospinal fluid testing.
The results of these experiments will help elucidate the link between AD and hearing loss by providing the first
reports of the perilymph proteome and cochlear pathology in patients with AD. Such evidence will help inform
the identification of new therapeutic targets for hearing loss as well as potential biomarkers for risk stratification
in this population.

## Key facts

- **NIH application ID:** 10940201
- **Project number:** 3U24DC020857-03S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Alan Gi-Lun Cheng
- **Activity code:** U24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,000
- **Award type:** 3
- **Project period:** 2022-09-16 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940201

## Citation

> US National Institutes of Health, RePORTER application 10940201, Human Ear Cellular Atlas (3U24DC020857-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10940201. Licensed CC0.

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