# Identification and Characterization of Senescent Cells in Molecular Subtypes of Alzheimer's Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $842,114

## Abstract

Alzheimer's disease (AD) remains uncurable. The complex, and diverse, neuropathology suggests that AD may
actually represent not a single disease, but a family of diseases that share plaque and tangle neuropathology.
The overall modest effects and variability among patients' response to the recent FDA approved drugs for the
treatment of AD highlight potential disease heterogeneity among study subjects. The high heterogeneity of AD
has also been strongly supported by the recent discovery of three major molecular subtypes of AD, each
possessing distinctive molecular signatures. The therapeutic strategy, referred to as “senolytics,” has gained
immense research attention for its hope to improve various age-associated conditions, including AD and related
dementias (ADRD), by pharmacologically removing senescent cells in the brain. Based on our preliminary
findings, there is compelling evidence indicating that senescence exhibits distinct characteristics in the major
molecular subtypes of AD. In this application, we propose to systematically investigate the molecular
mechanisms of brain senescence in different molecular subtypes of Alzheimer's Disease (AD) for discovery of
novel targets and therapeutics for AD. The project will be carried out by a multidisciplinary team of leading
scientists with expertise across translational Sen biology, neuropathology, bioinformatics, systems biology,
machine learning and artificial intelligence. We have successfully piloted, and here will deploy, a Sen multi-Omics
(senomic) pipeline to define
a
scale
molecular
the holistic cellular, molecular and chemical phenotypes of Sen cells in brains from
large number of AD and control subjects. In this project, we will systematically analyze all the existing large-
 single cell RNA-seq and multiome data in AD to identify and characterize senescent cells in major
subtypes of AD. We willvalidate key findings using single-cell multi-Omics and spatial transcriptomics
and imaging in which the entire human transcriptome can be profiled in single cells while maintaining spatial and
multi-scale resolution. Using our unique pipeline, we are very well positioned to characterize and quantify the
molecular heterogeneity of Sen cells in different AD subtypes. Our iterative approach involves profiling intact
tissues by 10xGenomics Visium and NanoString GeoMx and CosMx platforms as well as disaggregated cells by
single nucleus multi-Omics (RNA-seq and ATAC-seq). Results will provide a spatially resolved, comprehensive
molecular portrait of both chromatin accessibility, gene and protein expression in the hippocampus in AD in
contrast with healthy control. Our methodologies are non-destructive allowing for mapping multi-analytes back
to the tissues to determine cellular morphology and neighborhood environment. We will further develop novel
therapeutics against brain senescence in AD through cutting edge drug repositioning approaches. Key driver
genes and candidate drugs will be validated thro...

## Key facts

- **NIH application ID:** 10990629
- **Project number:** 1R01AG085182-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Miranda Ethel Orr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $842,114
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990629

## Citation

> US National Institutes of Health, RePORTER application 10990629, Identification and Characterization of Senescent Cells in Molecular Subtypes of Alzheimer's Disease (1R01AG085182-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10990629. Licensed CC0.

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