Mitochondrial DNA oxidative mutations are elevated in Mexican American women potentially implicating Alzheimer’s disease

Abstract

Mexican Americans (MAs) are the fastest-growing Hispanic population segment in the US; as this population increases in age, so will the societal burden of age-related diseases such as Alzheimer’s disease (AD). Mitochondrial DNA (mtDNA) damage may be implicated in MA AD risk since metabolic comorbidities are more prevalent in this group. Oxidative damage to guanosine (8oxoG) is one of the most prevalent DNA lesions and a putative indicator of mitochondrial dysfunction. Testing blood samples from participants of the Texas Alzheimer’s Research and Care Consortium, we found mtDNA 8oxoG mutational load to be significantly higher in MAs compared to non-Hispanic whites and that MA females are differentially affected. Furthermore, we identified specific mtDNA haplotypes that confer increased risk for oxidative damage and suggestive evidence that cognitive function may be related to 8oxoG burden. Our understanding of these phenomena will elucidate population- and sex-specific mechanisms of AD pathogenesis, informing the development of more precise interventions and therapeutic approaches for MAs with AD in the future.

Integrative Blood-Based Characterization of Oxidative Mitochondrial DNA Damage Variants Implicates Mexican Americans' Metabolic Risk for Developing Alzheimer’s Disease

“…AD disproportionately affects Hispanics/Latinos compared to NHWs; this is thought to be due to the increased prevalence of metabolic syndrome, obesity, cardiovascular health risks, and diabetes 9,17,18 . These observations combined with our previous data indicating MAs have elevated levels of oxidative damage compared to NHWs, leads us to the premise that mitochondrial health may hold greater biological importance in the development of age-related disease for individuals with Hispanic/Latinx ancestry 19 .…”

“…Our mtDNA CN and cf-mtDNA data can be considered as a proxy for our more recent data evaluating mitochondrial 8oxoG variant load since it does not capture if mutation has occurred. More recently in a similar population-based cohort, we discovered that mtDNA variants indicative of 8oxoG were signi cantly elevated in MAs compared to NHWs and was associated with sex, education, and suggestive for cognitive function 19 . Correspondingly, Miller, et al, revealed AD neurons compared to age-matched controls had signi cantly elevated levels of somatic single nucleotide variants (sSNVs) than anticipated when considering sSNVs are known to increase with age 32 , and the distribution of the variants are presumed to occur secondary to developing disease pathology 32 .…”

“…Previously derived 8oxoG variant load for each subject corresponding to 8oxoG "hotspots" 19 were further analyzed via multiple linear regression prediction models assessing a population × sex and years of education interaction effect, and a diabetes × cognition interaction effect was less informative than analyzing total 8oxoG variant count (Supplementary Tables 7 and 8). Population strati cation lost signi cant statistical associations (Supplementary Tables 9 and 10) that were observed in Supplementary Tables 7 and 8.…”

“…Identi cation of Variants Indicative of Oxidative Damage: The variant call les were manually assessed to identify 8oxoG transversions within the mitochondrial genome. The process of identifying these speci c oxidative transversions has been previously described 19 . Variants indicative of 8oxoG damage for each subject from the buffy coat portion were summed and normalized by accounting for read depth (variant count per 1000 read depth) to evaluate group differences based on the following variables: population, cognition, sex, type-2 diabetes, comorbidity (cognitive impairment and diabetes), both APOE and OGG1 genotype, and lifestyle factors.…”

Is Mitochondria DNA Variation a Biomarker for AD?

“…In Mexican Americans, the mtDNA 8oxoG mutation load was significantly higher when compared to non-Hispanic whites. Haplogroups A and C exhibited higher 8oxoG variant counts, while haplogroups I and K exhibited lower 8oxoG variant counts [ 61 ]. All these findings suggest that mtDNA haplogroups are associated with the risk of AD, but it is highly specific to populations.…”