# Large-Scale Genomic Analysis of Aging-Related Cognitive Change Prior to Dementia Onset

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $655,978

## Abstract

PROJECT SUMMARY
Major Neurocognitive Disorders of Aging, including Alzheimer's Disease (AD) and Alzheimer's Disease
Related Dementias (ADRD), produce cognitive declines that substantially affect daily living. To date, the
molecular processes underlying the neurodegeneration and cognitive declines that ultimately give rise to
AD/ADRD remain poorly understood. Recent developments in genome wide association study (GWAS)
provide promising avenues for identifying genetic variants and associated biological pathways of AD/ADRD
risk beyond those characterized by polymorphisms within the well-known APOE gene. However, a major
challenge to progress in AD/ADRD genomics is that contemporary methods used to diagnose AD/ADRDs for
epidemiological research often rely on cognitive assessments or clinical rating at a single point in time, which
are confounded by substantial variation in peak levels of cognitive function in early adulthood. Particularly
when peak levels of cognitive function are high, cognitive declines may go undetected for decades before
individuals present with impaired levels of functioning. Indeed, it has now become clear that by the time
AD/ADRD diagnoses are made, the pathophysiology of AD/ADRD and trajectories of accelerated cognitive
decline have accumulated extensively, during a so-called “silent period.” These issues both dilute and bias
GWAS associations in conventional case-control, time-to-event, age-at-event, and single occasion designs.
The primary goal of the current R01 proposal is therefore to conduct the first large-scale consortium-based
GWAS of continuous rates of longitudinal aging-related cognitive change prior to dementia onset. This will
allow us to identify variants beyond those in the APOE gene that confer risk for rate of cognitive decline leading
to eventual AD/ADRD, estimate improved genome-wide polygenic scores that can be used to enhance
assessment of AD/ADRD risk, and identify novel biological pathways of AD/ADRD risk that can be targeted by
prevention and treatment efforts.

## Key facts

- **NIH application ID:** 10891784
- **Project number:** 4R01AG073593-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Elliot Max Tucker-Drob
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $655,978
- **Award type:** 4N
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891784

## Citation

> US National Institutes of Health, RePORTER application 10891784, Large-Scale Genomic Analysis of Aging-Related Cognitive Change Prior to Dementia Onset (4R01AG073593-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891784. Licensed CC0.

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