# Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $1,224,616

## Abstract

Project Summary
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Pathologically, AD is characterized by
amyloid plaques and neurofibrillary tangles. Clinically, AD patients present with progressive memory decline
followed by deterioration of other cognitive domains and activities of daily living. Advanced age is the greatest
risk factor. No effective method is available for preventing and/or treating this devastating disease. However,
certain individuals of the elder population (≥ 85 years) remain cognitively intact, including some with substantial
plaques and neurofibrillary tangle burdens, the two pathological hallmarks for fully symptomatic AD. The
mechanisms of cognitive resilience and protection against AD in these elderly persons remain elusive. This
proposal brings together scientists and postmortem human brain tissue samples from two major AD-research
centers (the Icahn School of Medicine at Mount Sinai and the Rush University Medical Center) and aims to
systematically identify and validate genetic variants, genes, proteins, and molecular networks underlying
cognitive resilience to AD risk and proposes to build a comprehensive unbiased signaling pathway map
underlying cognitive resilience to AD. Towards this end, we will develop an AD resilient cohort comprised of
genetic, transcriptomic and proteomic data in the prefrontal cortex from a large number of brains in four
categories: 1) very old (age of death (AoD) ≥ 85) AD-resilient, 2) young (AoD < 85) healthy, 3) very old (AoD
≥85) AD and 4) young (AoD < 85) AD. We will perform systems genetics and integrative network biology
analyses on the large-scale high-dimensional molecular profiling data to identify genetic variants, genes,
proteins, and molecular networks underlying cognitive resilience to AD risk. We will systematically validate key
drivers of the molecular networks underlying the cognitive resilience to AD using two diverse (C. elegans and
mouse) model systems. We will validate the structures of AD-resilient molecular networks for building a data-
driven, comprehensive signaling pathway map underlying cognitive resilience to AD risk. In particular, we will
test the hypotheses that enhanced mitochondrial function and immune competence as well as their underlying
molecular networks confer cognitive resilience. Our study will not only present a global landscape of the
interplays among genetic variants, mRNAs and proteins responsible for cognitive resilience to AD but also
pinpoint critical network structures and key drivers that can potentially lead to development of novel prevention
strategies in combating AD.

## Key facts

- **NIH application ID:** 9949596
- **Project number:** 5R01AG057907-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** MICHELLE E EHRLICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,224,616
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949596

## Citation

> US National Institutes of Health, RePORTER application 9949596, Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease (5R01AG057907-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9949596. Licensed CC0.

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