# Contribution of somatic mitochondrial DNA mutation to the transition from normal aging to Alzheimers disease

> **NIH NIH K01** · UNIVERSITY OF WASHINGTON · 2024 · $121,392

## Abstract

Project Summary/Abstract: Contribution of somatic mitochondrial DNA mutation to the transition from
normal aging to Alzheimer’s disease.
Candidate and Training: Dr. Sanchez-Contreras is an MD, PhD, Acting Instructor in the Department of
Laboratory Medicine and Pathology, University of Washington (UW). Her research is directed towards
understanding the effects that somatic mutations of the mitochondrial DNA (mtDNA) have on mitochondrial
function during aging, and further differentiate these from pathogenic mtDNA mutations that cause
mitochondrial dysfunction in Alzheimer’s disease (AD). To develop her area of research, Dr. Sanchez-
Contreras will apply her expertise in duplex sequencing and in neurodegeneration, while she will acquire skills
in procedures to measure mitochondrial physiology and data analysis. This training will be focused on the
underlying mitochondrial biology of aging guided by four mentors that are experts in mitochondrial genetics and
biology, neuropathology and in vivo models of aging and AD and immersed in a research group that is a leader
in aging and in AD research in the country.
Research: Somatic mutations of the mtDNA and mitochondrial dysfunction are found in the brain of AD
patients. As these findings also accompany normal aging, it is unclear what determines the departure from
normal to pathogenic in AD. The main hypothesis of this study is that somatic mtDNA mutations abnormally
increase at preclinical and early stages of AD, and that they contribute to mitochondrial and synaptic
dysfunction, and the worsening of AD pathology. This hypothesis will be tested in two aims. In Aim 1, pre-
clinical AD patients will be studied to find somatic mutations and mitochondrial and synaptic abnormalities that
associate with AD pathology. In Aim 2, a systematic evaluation of somatic mtDNA mutation and mitochondrial
function will be performed in the mouse brain by increasing somatic mutagenesis at multiple ages using the
mutator mito-APOBEC1 transgene. Lastly, the impact of somatic mutation in AD will be studied in two models
of the main neuropathological components: amyloid pathology and tauopathy. These two approaches will
contribute to understanding of how the entorhinal cortex and the hippocampus respond to increasing somatic
mutations and mito-dysfunction early in the progression of AD.
Career Development Plan: The execution of this K01 award is designed to ensure Dr. Sanchez-Contreras’
successful transition to an independent faculty position in her department. To this aim, a structured plan is
presented that includes the commitment of her institution and her department to support her efforts, a strong
mentorship committee, the consolidation of strategic collaborations and the performance of crucial
experimental protocols that will result in significant advancements in the field of aging and that will be the
foundation for R21 and R01 submissions at the conclusion of this K01.

## Key facts

- **NIH application ID:** 10841024
- **Project number:** 5K01AG073470-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Monica Yicette Sanchez-Contreras
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $121,392
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841024

## Citation

> US National Institutes of Health, RePORTER application 10841024, Contribution of somatic mitochondrial DNA mutation to the transition from normal aging to Alzheimers disease (5K01AG073470-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10841024. Licensed CC0.

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