# Associations of Mitochondrial DNA Alterations with Alzheimer's Disease Related Brain Health

> **NIH NIH K99** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $96,589

## Abstract

ABSTRACT
Dementia is a major global health challenge that lacks effective treatment and early diagnosis tools. Alzheimer’s
disease (AD) comprises 70% of all dementia syndromes. The Lancet Commission recently urged a life-course
model of AD prevention, providing impetus for the development of scalable early biomarkers. Mitochondria play
a critical bioenergetic role in maintaining physiologic homeostasis, particularly for high energy demand organs,
like the brain. Mitochondrial DNA (mtDNA) copy number (mtDNA-CN), a quantitative indicator of mitochondrial
function, is strongly associated with AD in older adults. Growing evidence also implicates mtDNA mutation load,
or mtDNA heteroplasmy (mtDNA-Het), in AD. Despite the accumulating evidence for a key role of these blood
indicators in cognitive decline and AD in older adults, there is a paucity of research examining their relationships
in midlife, a critical time when preventive interventions may be most effective. Moreover, the relationships
between these mtDNA alterations and early emerging AD-related neurobiological substrates is unclear. While
cardiovascular disease (CVD) risk factors have also been associated with mtDNA alterations, the temporal
associations are not fully discerned. Whether mtDNA alterations could mediate the well-known but less well
understood associations of heart and brain health is unknown. Our central hypothesis is that mtDNA alterations
are associated with cognitive decline and AD-related neurobiological substrates in midlife and mediate the
associations of early life CVD risk factors with midlife brain health. To test this hypothesis, we will leverage life-
long measures of CVD risk factors and two midlife measures of cognitive function in the full Bogalusa Heart
Study (BHS) cohort (N=1,298; 850 whites and 448 Blacks), along with AD-related neurobiological substrates
from brain magnetic resonance imaging (MRI) and photon emission tomography (PET) scans available in a
large subsample at midlife (N=700). Within the BHS, we further propose measurement of mtDNA alterations at
two midlife time-points. Our well-powered validation effort will be conducted among diverse participants from the
Trans-Omics for Precision Medicine program (N=3,724) with existing data. These resources will allow us to
examine the prospective and temporal associations of mtDNA alterations with cognitive decline (Aim 1) and
neurobiological substrates in midlife (Aim 2); and assess prospective and temporal associations of early life
CVD risk factors with mtDNA and investigate mediating effects of mtDNA on associations of childhood CVD risk
factors with midlife brain health (Aim 3). Our work could have broad impacts on population-wide and targeted
efforts to curb dementia, informing drug development and risk stratification. The K99 training will allow me to
conduct the first study examining prospective associations of midlife mtDNA with cognitive decline. Mentored by
a team of experts in epidemiology, genom...

## Key facts

- **NIH application ID:** 10906984
- **Project number:** 5K99AG083214-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Yang Pan
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $96,589
- **Award type:** 5
- **Project period:** 2023-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906984

## Citation

> US National Institutes of Health, RePORTER application 10906984, Associations of Mitochondrial DNA Alterations with Alzheimer's Disease Related Brain Health (5K99AG083214-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10906984. Licensed CC0.

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