# Exploring Common Biological Pathways Underlying Insulin Resistance and Alzheimer Disease using Genetic and Omic Tools

> **NIH NIH K99** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2022 · $89,424

## Abstract

Project Summary / Abstract
Insulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) but the mechanisms by which IR
predisposes to AD is unknown, notably, if IR is causally related to AD and which regulatory mechanisms
underlie IR and contribute to AD. The proposal is designed to address these critical gaps in scientific
knowledge by using omics to evaluate the causal relationship of IR on AD and to reveal new regulatory
mechanisms involved in IR and AD. The Principal Investigator (PI), Dr. Sarnowski, is a statistical geneticist and
an early career investigator with a research focus on the identification of genetic and environmental risk factors
of complex traits. The long-term goal of this project is to identify individuals who will benefit from treatments
improving insulin sensitivity to better prevent, delay or stop the progression of AD. The overall objective is to
better characterize mechanisms by which IR contributes to AD and evaluate how they may differ from known
mechanisms involved in AD pathogenesis. The central hypothesis is that omics will help to better understand
and characterize the relationships between IR and AD. The rationale is that omics will help to disentangle the
mode of action of IR on AD and identify targets for preventive and therapeutic interventions. Guided by strong
preliminary results in the Framingham Heart Study, the hypothesis will be tested through three specific aims: 1)
Determine if IR is causally related to AD in a Mendelian Randomization (MR) framework with various genetic
instrument variables (IVs); 2) Characterize molecular signatures of IR associated with AD using brain and blood
omic data; and 3) Develop a joint test to evaluate the genetic contribution at IR signatures associated with AD.
In Aim 1, genetic IVs, including standard and pathway-specific genetic risk scores and predictors identified by
machine learning, will be constructed to evaluate the causal relationships between IR and AD using various MR
methods. In Aim 2, association analyses will be performed to identify brain and blood omic signatures of IR
related to AD. In Aim 3, new integrative statistical methods leveraging annotations will be developed to evaluate
the genetic contribution on omics at loci involved in IR and AD. Career development activities will include training
in AD pathophysiology, multi-omic analysis and machine learning techniques through coursework, seminars,
mentorship, and collaborations with a team of leading expert scientists. The approach is innovative by shifting
focus to omics to study the regulatory mechanisms involved in IR and AD. The proposed research is significant
as the expected outcomes will contribute to a better understanding of how insulin sensitivity can be improved to
better prevent, delay or stop the progression of AD, reduce cognitive decline and prevalence of dementia due to
AD, and promote brain health in late life. The experience acquired in achieving the aims of this grant will...

## Key facts

- **NIH application ID:** 10373944
- **Project number:** 5K99AG066849-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Chloe Sarnowski
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $89,424
- **Award type:** 5
- **Project period:** 2021-04-01 → 2022-08-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373944

## Citation

> US National Institutes of Health, RePORTER application 10373944, Exploring Common Biological Pathways Underlying Insulin Resistance and Alzheimer Disease using Genetic and Omic Tools (5K99AG066849-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10373944. Licensed CC0.

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