# Genetic and Environmental Drivers of Cognitive Resilience in Aging Populations

> **NIH NIH F99** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $46,752

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease and related dementias (ADRD) are major sources of health, social, and economic burden.
The lack of effective ADRD therapies or strategies to prevent or stop ADRD progression presents a significant
public health challenge in the context of aging populations. A focus on resilience, instead of disease, may
provide insight into novel treatment and prevention modalities. Cognitively resilient individuals typically retain
normal cognitive function despite advanced age or brain pathology. The genetic architectures of cognitive
resilience and Alzheimer's disease appear distinct based on recent genomic work. However, further
interrogation of the biologic basis of cognitive resilience, including the interplay between genetic and
environmental factors, is necessary to design targeted interventions that build cognitive resilience in older
adults. We posit that a multi-omics approach can identify novel cognitive resilience loci and elucidate pathways
that promote cognitive resilience and lower the risk of ADRD. We propose to use extant genomic data, high-
quality longitudinal measurements of 5,000 plasma proteins, repeat psychometric assessments, and
neuroimaging in the Atherosclerosis Risk in Communities (ARIC) study to accomplish the following specific
aims: (1) employ a multi-omic approach to identify causal loci and biomarkers for cognitive resilience in
community-dwelling older adults and (2) decompose the genetic and environmental drivers of cognitive
resilience. In Aim 1, we will conduct a proteome-wide association study (PWAS) to identify proteins associated
with cognitive resilience. Given heterogeneity in the measure of cognitive resilience in epidemiologic studies,
we will use psychometric and imaging-based definitions of cognitive resilience. We will also identify protein
quantitative trait loci, perform fine-mapping, and use Mendelian Randomization to identify causal markers of
cognitive resilience. In Aim 2, we will build and validate a polygenic risk score (PRS) for cognitive resilience.
The PRS will be applied to model the interplay of genetic and modifiable environmental factors on cognitive
resilience. This award will support my transition to aging research and my immediate and long-term goals
through (1) advanced training in molecular, neuro-, and aging epidemiology and (2) the mentored application of
these methods in an innovative research question aligned with priorities in population aging research. With the
dedication of a highly qualified and enthusiastic team of mentors, the successful completion of these aims will
deepen the field's understanding of the determinants of cognitive resilience. Further, the training objectives
nested in the F99 and K00 phases of this award will prepare me for a career in which I will lead an
interdisciplinary team as an independent investigator in aging research

## Key facts

- **NIH application ID:** 10478185
- **Project number:** 5F99AG073565-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Alvin G. Thomas
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478185

## Citation

> US National Institutes of Health, RePORTER application 10478185, Genetic and Environmental Drivers of Cognitive Resilience in Aging Populations (5F99AG073565-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10478185. Licensed CC0.

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