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.