# Blood mitochondrial DNA biomarkers of midlife cognitive decline and adverse brain imaging changes - A longitudinal investigation in the CARDIA population-based cohort study

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $751,384

## Abstract

SUMMARY
Alzheimer’s disease and related dementias (ADRDs) are typically the result of neurodegenerative processes
that begin 15-20 years before clinical diagnosis. Despite this lengthy subclinical phase and advances in early
diagnostic technologies including cerebrospinal fluid (CSF) biomarkers, brain MRIs, and positron emission
tomography (PET) measures there are no scalable biomarkers to identify individuals with preclinical disease,
which may offer the best time window for intervention. Specifically, because brain MRI and PET tests are
resource-intensive and CSF sampling is invasive, there is urgent need for biomarkers based on blood samples,
which can be non-invasively collected even in centers lacking highly specialized technology.
The mitochondrial genome (mtDNA), unlike the stable nuclear genome, is dynamic and accumulates somatic
mutations over the lifespan. Mutations in the mtDNA can be induced by oxidative stress and lead to declining
mitochondrial function as we age; in turn, less functional mitochondria generate higher levels of oxidative stress,
which induces chronic inflammation and tissue injury in specific organs including the brain. Yet, no study has
investigated mtDNA mutations as early predictors of ADRD. We hypothesize that individuals with higher levels
and faster accumulation of blood mtDNA mutations have greater cognitive decline and preclinical ADRD brain
imaging changes during midlife, and that these mtDNA biomarkers will predict ADRD diagnosis in older adults.
We will test our hypotheses by leveraging the NHLBI-funded Coronary Artery Risk Development In young
Adults (CARDIA) study. CARDIA is a multicenter, community-based, longitudinal cohort that recruited 5,115
black and white young adults (mean age 25 years), followed them up at least every five years, and is preparing
to conduct its examination Year 35 (Y35) visit in 2020/21 (mean age 60 years) when over 3,000 participants
are expected to return. We will use state-of-the-art deep sequencing technology to measure mtDNA mutations
in CARDIA blood samples collected at Y15, Y25, and Y35. In Aim 1, we will determine whether higher levels of
mtDNA mutations and their accumulation over time are associated with greater cognitive decline in midlife. In
Aim 2, we will determine whether mtDNA mutations are associated with structural, physiological, and functional
MRI phenotypes of preclinical ADRD as well as with sensitive MRI-based markers of accelerated brain aging
and preclinical ADRD constructed by our team using contemporary machine learning techniques. Finally, in
Aim 3, we will test the clinical utility of these mtDNA mutation biomarkers in identifying individuals at risk of
future ADRD in four older cohorts that have large numbers of longitudinally identified, clinically-diagnosed
ADRD. Our focus on longitudinal measures of blood mtDNA, cognitive function, and MRI changes over a 10-
year period during midlife, combined with characterization of their clinical utility in o...

## Key facts

- **NIH application ID:** 11229428
- **Project number:** 7R01AG069120-06
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Lifang Hou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $751,384
- **Award type:** 7
- **Project period:** 2020-07-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11229428

## Citation

> US National Institutes of Health, RePORTER application 11229428, Blood mitochondrial DNA biomarkers of midlife cognitive decline and adverse brain imaging changes - A longitudinal investigation in the CARDIA population-based cohort study (7R01AG069120-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11229428. Licensed CC0.

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