# Genetic Drivers of Resilience to Alzheimer's Disease

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $779,990

## Abstract

Abstract
As the population ages, late-onset Alzheimer's disease (AD) is becoming an increasingly important public
health issue. Clinical trials targeted at reducing AD progression have demonstrated that patients continue to
decline despite therapeutic intervention. Thus, there is a pressing need for new treatments aimed at novel
therapeutic targets. A shift in focus from risk to resilience has tremendous potential to have a major public
health impact by highlighting mechanisms that naturally counteract the damaging effects of AD
neuropathology. Interestingly, at autopsy, approximately 30% of cognitively normal individuals have the
pathological features of AD. Research from both our group and others has begun to uncover genetic factors
that explain some of the observed disconnect between neuropathology and clinical dementia. However, small
sample sizes have limited advances in characterizing the heritability and genetic architecture of resilience in a
comprehensive manner. Therefore, this project will perform a large, comprehensive analysis of genetic
resilience by integrating in vivo biomarker and autopsy data into a unified model of resilience. We propose to
leverage a Vanderbilt resource called the Resilience from Alzheimer's Disease (RAD) database to uncover
novel protective genetic effects. In RAD, we have developed and validated continuous metrics of resilience that
quantify the degree to which an individual is resilient to both the cognitive deficits and the neurodegeneration
associated with AD neuropathology. Our strong interdisciplinary team is uniquely positioned to characterize the
genetic architecture of resilience leveraging the infrastructure and rich data resources of the AD genetic
consortium and the AD sequencing project. We will identify and replicate common and rare genetic variants
that predict protection from cognitive impairment and protection from neurodegeneration. Additionally, we will
integrate known sex differences in the downstream consequences of AD neuropathology to identify sex-
specific genes and pathways that promote resilience. The genes and pathways identified will offer novel
therapeutic targets for intervention aimed at activating compensatory mechanisms that confer resilience to the
damaging effects of AD neuropathology.

## Key facts

- **NIH application ID:** 10207465
- **Project number:** 5R01AG059716-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Timothy J Hohman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $779,990
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207465

## Citation

> US National Institutes of Health, RePORTER application 10207465, Genetic Drivers of Resilience to Alzheimer's Disease (5R01AG059716-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10207465. Licensed CC0.

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