# An Integrative Multi-Omics Approach to Elucidate Sex-Specific Differences in Alzheimers Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $818,155

## Abstract

PROJECT SUMMARY
 Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by interactions among
multiple genetic and environmental factors. A large body of evidence has convincingly demonstrated that sex is
a major source of disease heterogeneity and physiologic status. Sex differences in the risk of AD, vulnerability
to apolipoprotein (apo) E genetic load, and severity of AD pathology burden have been established. In addition
to these direct contributors to disease, sex-differences also exist for many of the physiological and co-morbid
conditions known to be risk factors for AD, most notably age-related inflammation. Although the sex differences
in the risk of AD, vulnerability to genetic load and severity of AD pathology burden have been well established,
the molecular underpinnings and pathways that are differentially mediated in male and female AD patients are
still poorly understood. The difference in immunity and inflammatory response during AD process is another
source of the disease heterogeneity; however, the underlying mechanisms remain elusive.
 Precision medicine is an emerging integrative approach for disease prevention, early detection, and
treatment, which takes into account individual variability in genetics, epigenetics, sex, environment, and
lifestyle. The current and ever-growing availability of public `omics data of normal and AD brains, including
Gene Expression Omnibus, Array Express and the new National Institute of Aging's Accelerating Medicines
Partnership for Alzheimer's Disease portal (AMP-AD), along with emerging single cell sequencing technologies
and computational tools to dissect molecular drivers of disease at a network level, present a unique new
opportunity to query the interactive effects of apoE4 with sex and inflammation on AD pathogenesis at the
genomic, transcriptomic and single cell level.
 By capitalizing on this promise, this proposal aims (1) to analyze publicly available, large-scale
transcriptomic datasets of AD patients and age-matched controls to identify sex and apoE genotype-specific
gene expression signatures of AD, (2) to analyze publicly available, large-scale genomic datasets of AD
patients and age-matched controls to identify genomic regions that are associated with AD differentially in male
and female patients and examine their interactive effects with apoE genotypes, and (3) to leverage single
nucleus RNA-Seq technology to examine sex and apoE genotype specific transcriptomic signatures in an
established mouse model of AD and evaluate their relevance to human data. We aim to specifically interrogate
inflammatory and immune pathways both on the genomic and transcriptomic level in mice and humans
throughout our three specific aims to elucidate the mechanisms by which these pathways lead to the disease
and genotype specific differences in men and women with AD.The outcomes of the proposed studies will shed
light on the molecular pathways that might explain the sex differen...

## Key facts

- **NIH application ID:** 10172820
- **Project number:** 5R01AG060393-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** MARINA SIROTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $818,155
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172820

## Citation

> US National Institutes of Health, RePORTER application 10172820, An Integrative Multi-Omics Approach to Elucidate Sex-Specific Differences in Alzheimers Disease (5R01AG060393-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10172820. Licensed CC0.

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