Characterization of Mitochondrial DNA Damage in Complex Disease Using Two Different NGS Platforms

Purpose: The Hispanic/Latinx aging (65+) population is expected to increase through 2060 causing the number of Alzheimer's Disease (AD) cases in the Hispanic/Latinx population to quadruple. Several risk factors for developing cognitive impairment are prevalent among Mexican Americans (MAs), although the etiology of these associations remains unclear. Age-associated decline in mitochondrial function results in accumulation of reactive oxygen species (ROS) capable of damaging essential biomolecules, including DNA. The mitochondrial genome is particularly vulnerable to DNA damage, which has a strong correlation with AD pathology. Developing an improved method to assess mitochondrial oxidative damage may help resolve the potential association between abnormal mitochondrial function as indicated by oxidative DNA damage in cognitively impaired MAs. Oxidative damage to guanine (G) forming 8oxoG, is one of the most prevalent DNA lesions. Current methods for detection are limited and lack reproducibility. Lifestyle and/or metabolic health may contribute directly to age-related neurodegeneration. Methods: We aim to investigate the mutational load indicative of oxidative DNA damage in MAs compared to non-Hispanic white (NHW) participants in a human AD cohort, TARCC, who were diagnosed with AD, type-2 diabetes (T2D), and comorbidity (AD/T2D) using Illumina-based NGS. Additionally, we propose nanopore sequencing technology as an improved alternative to current detection/quantification methods. Results: We describe preliminary proof-of-concept results and future applications of this method to analyze mtDNA damage in participants of TARCC. Conclusion: Investigation of oxidative DNA damage may aid our understanding of the differences in manifestation of age-related dementia in MAs.