# Mitochondrial DNA Copy Number and Sequence Variation in Relation to Age, Alzheimer's Disease Related Phenotypes and Age-related Metabolic Traits

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $635,620

## Abstract

Abstract
Aging is the main risk factor for many chronic diseases, including late onset Alzheimer's disease (LOAD) and
many age-related metabolic diseases, such as obesity and diabetes. Using AD as an example, the number of
people with AD doubles every 5 years beyond age 65. In 2017, 5.3 million Americans 65 years or older are
affected by LOAD. The burden of health care costs for LOAD is enormous – $259 billion in 2017. Thus, early
detection and treatment of these age-related diseases should be a core tenet of public health. Research is
needed to guide such efforts.
Over the last decade, accumulating evidence has linked aging to mitochondrial dysfunction. Mitochondria are
tiny powerhouses, generating more than 90% of energy to support normal cellular function. Mitochondria contain
their own genome (mtDNA) which is both polymorphic and heteroplasmic, i.e., two or more mtDNA alleles can
co-exist in the same cell due to the presence of many mtDNA molecules within any cell. Previous studies in
Europeans have found that reduced mtDNA copy number was associated with frailty and higher mortality among
elderly. Furthermore, reduced mtDNA copy number in human cerebrospinal fluid was observed at least a decade
before clinic AD symptoms develop. These findings in Europeans need to be generalized in other ethnic groups.
Several hundreds of mtDNA rare mutations have been described to cause mostly rare, yet severe maternally
inherited diseases. A limited number of common mtDNA polymorphisms were examined in relation to metabolic
disorders, dementia and cognitive functions. Robust associations, however, haven't been established between
common mtDNA polymorphisms and age-related common diseases. In most of these previous studies,
heteroplasmic mtDNA mutations haven't been well studied with respect to aging and age-related human
diseases because, until recently, sequencing has been extremely costly. Studying a spectrum of mtDNA
mutations along with mtDNA copy number in relation to age-related traits in large samples has now become
possible thanks to drastically decreased whole genome sequencing costs.
This proposed study will leverage five prospective cohorts, each with whole genome sequencing data generated
from the National Heart, Lung and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) and
extensive cognitive, brain structure, and cardiometabolic measures. The expected outcomes of the work
proposed are to 1) develop a novel statistical method to identify age-related heteroplasmic (i.e., somatic) mtDNA
mutations, and 2) develop a statistical framework to analyze mtDNA copy number and heteroplasmic mutations
in relation to key age-related disorders, include LOAD and age-related metabolic traits. Results of this
investigation are expected to advance understanding of the role of aging on the mitochondrial genome, and in
turn, the contributions of mitochondrial genome to age-related traits. Equally important, a positive impact of this
project wil...

## Key facts

- **NIH application ID:** 10212947
- **Project number:** 5R01AG059727-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Chunyu Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $635,620
- **Award type:** 5
- **Project period:** 2018-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212947

## Citation

> US National Institutes of Health, RePORTER application 10212947, Mitochondrial DNA Copy Number and Sequence Variation in Relation to Age, Alzheimer's Disease Related Phenotypes and Age-related Metabolic Traits (5R01AG059727-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10212947. Licensed CC0.

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