Investigating Oxidative Damage: Implications in Cognitive and Metabolic Phenotypes of Alzheimer's Disease in the Mexican American Population

The elderly population is rapidly expanding leading to increases in age-related diseases such as cardiovascular disease, metabolic disorders, cancer, and neurodegenerative diseases. The Texas Alzheimer's Research and Care Consortium (TARCC) is a collaborative research effort to identify factors involved in the development and progression of Alzheimer's Disease (AD) in Mexican Americans (MAs). In the MA population, diabetes, depression, stroke, and obesity are common risk factors for developing cognitive impairment. The reasons for the association between cognitive decline and comorbidities remain unclear. Studies have shown correlations between common pathological changes observed in AD and those that are a result of DNA damage. The mitochondrial genome is particularly vulnerable to DNA damage due to its close proximity to reactive oxygen species (ROS). Age associated declines in mitochondrial function results in accumulation of ROS, which are capable of damaging DNA and other essential biomolecules. Oxidative damage to DNA takes many forms, however oxidation of guanine (G) forming 8oxoG, is one of the most prevalent DNA lesions. Currently, the methods for detection of 8oxoG are limited and lack reproducibility due to several reasons. We propose nanopore sequencing technology as an improved alternative to current detection and quantification methods. Here we describe preliminary proof of concept results and discuss future applications of this method for analysis of mtDNA damage in participants of the TARCC cohort. Investigation of oxidative DNA damage may aid our understanding of the differences in manifestation of age-related cognitive decline in Mexican Americans as compared to non-Hispanic whites.