# Administrative Supplement to R21AG058052: Bioenergetic dysfunction in the aging, injured brain: characterization and intervention with creatine

> **NIH NIH R21** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $217,135

## Abstract

Administrative Supplement Request to R21AG058052-01A1, “Bioenergetic dysfunction in the aging,
injured brain: characterization and intervention with creatine”
Abstract
A history of traumatic brain injury (TBI) is one of the strongest risk factors for Alzheimer's disease and related
dementias (AD/ADRD), and evidence suggests that older age at the time of TBI augments the risk. However,
the biological mechanisms linking TBI and AD/ADRD—and how these might interact with aging—remain
unknown. Our laboratory studies the effects of older age on the pathophysiology of TBI in animal models. Our
parent grant (R21AG058052-01A1) aims to i) establish the effects of older age on the brain's bioenergetic
response to TBI, and ii) manipulate this response with a dietary creatine treatment, comparing therapeutic
efficacy across age and sex. While previous studies have shown that TBI can rapidly induce changes in brain
amyloid beta (Aβ) and tau proteostasis, little is known about how older age at the time of injury may affect the
development of Aβ and tau pathology. To address this knowledge gap, we propose a direct extension of our
parent grant that will examine post-TBI changes in brain Aβ and tau proteostasis as a function of age. Since
not all TBI survivors develop aging-related dementia, biomarkers of post-TBI AD risk are needed. Recent
evidence has linked elevated circulating cell-free mitochondrial DNA (mtDNA) to TBI severity and patient
outcomes, and also to mechanisms of AD/ADRD pathogenesis. We will assess post-TBI changes in blood and
CSF cell-free mtDNA as a function of age, and our exploratory study will investigate the possibility that mtDNA
constitutes a novel biomarker of post-TBI risk of AD.
The proposed studies represent a natural extension of our ongoing research on the bioenergetic response to
TBI in the aging brain. Work performed under this supplement will add new knowledge to the still-nascent field
of research on the link between TBI and AD/ADRD. The proposed experiments will generate a strong body of
preliminary data to support a planned R01 application on mtDNA as a possible link between TBI, aging, and
mechanisms of AD/ADRD pathogenesis. These studies are therefore directly responsive to NOT-AG-20-008.

## Key facts

- **NIH application ID:** 10123949
- **Project number:** 3R21AG058052-02S1
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** JANNA Leigh HARRIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $217,135
- **Award type:** 3
- **Project period:** 2019-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123949

## Citation

> US National Institutes of Health, RePORTER application 10123949, Administrative Supplement to R21AG058052: Bioenergetic dysfunction in the aging, injured brain: characterization and intervention with creatine (3R21AG058052-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10123949. Licensed CC0.

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