# Systems Genetics Analysis of Resilience to Alzheimer’s disease

> **NIH NIH R01** · JACKSON LABORATORY · 2020 · $1,050,920

## Abstract

PROJECT SUMMARY
Cognitive resilience to Alzheimer's Disease (AD) is a phenomenon whereby individuals are resistant to its most
damaging effects on cognition, despite the presence of known familial AD (FAD) mutations or advanced
neuropathology. Genetic factors promoting cognitive resilience may thus provide key targets for treatment and
prevention of AD. Our overall objective is to identify drivers of cognitive resilience by using network approaches
to integrate data collected from mouse FAD models with human AD data. To this end, we will in Aim 1 use a
novel mouse panel that incorporates high-risk human FAD mutations on a segregated background of genetic
diversity (BXD panel) to identify modifiers that contribute to AD resilience in a `humanized' mouse population.
High-dimensional molecular, cognitive and pathologic data from these mice will be integrated to predict
resilience factors and networks using causal inference analyses. In Aim 2, we will test two set of genes for
association with resilience in humans with asymptomatic AD: 1) a previously validated list of genes identified
by proteomics and behavioral analyses to be associated with exceptional cognitive longevity in mice and 2)
novel genes and networks implicated by our analyses in Aim 1. In Aim 3, we will validate resilience factors and
determine their effects on memory-relevant brain networks in powerful AD mouse models, testing both novel
candidates identified in Aims 1 and 2 and a priori candidates (e.g., Trpc3, Adamts17 and Hp1bp3). This project
will deliver novel, validated targets for promoting healthy brain aging and resilience to AD. Moreover, we will
provide mechanistic insight into AD resilience, specifically supporting or refuting our hypothesis that modifiers
of cognition in FAD similarly influence late-onset AD by preserving the functional connectivity of memory
relevant networks. We will annotate, curate, and rapidly disseminate the data to the broad scientific community
prior to publication via the NIA-supported AMP-AD Knowledge Portal to maximize the usability of these data for
meta-analysis and systems biology research.

## Key facts

- **NIH application ID:** 9962269
- **Project number:** 5R01AG057914-04
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** CATHERINE COOK KACZOROWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,050,920
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962269

## Citation

> US National Institutes of Health, RePORTER application 9962269, Systems Genetics Analysis of Resilience to Alzheimer’s disease (5R01AG057914-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962269. Licensed CC0.

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