Blood-Based mtDNA Quantification Indicates Population-Specific Differences Associated with Alzheimer’s Disease-Related Risk

Article type: Research Article

Authors: Gorham, Isabelle K.^a | Reid, Danielle Marie^a | Sun, Jie^a | Zhou, Zhengyang^b | Barber, Robert C.^{c; d} | Phillips, Nicole R.^{a; d; *}

Affiliations: [a] Department of Microbiology, Immunology, and Genetics, School of Biomedical Sciences, UNT Health Science Center, Fort Worth, TX, USA | [b] Department of Biostatistics and Epidemiology, School of Public Health, UNT Health Science Center, Fort Worth, TX, USA | [c] Department of Family Medicine, Texas College of Osteopathic Medicine, UNT Health Science Center, Fort Worth, TX, USA | [d] Institute for Translational Research, UNT Health Science Center, Fort Worth, TX, USA

Correspondence: [*] Correspondence to: Nicole R. Phillips, Assistant Professor Department of Microbiology, Immunology, and Genetics, School of Biomedical Sciences, UNT Health Science Center, Fort Worth, TX, USA. E-mail: Nicole.Phillips@unthsc.edu.

Abstract: Background:Age is known to be the biggest risk factor for Alzheimer’s disease (AD), and Mexican Americans (MAs), who are one of the fastest-aging populations in the United States, are at a uniquely elevated risk. Mitochondrial stress and dysfunction are key players in the progression of AD and are also known to be impacted by lifestyle and environmental exposures/stressors. Objective:This study aimed to identify population-specific differences in indicators of mitochondrial stress and dysfunction associated with AD risk that are detectable in the blood. Methods:Examining blood from both non-Hispanic white (NHW) and MA participants (N = 527, MA n = 284, NHW n = 243), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) copy numbers were assessed through quantitative PCR. Data was stratified by population and sample type, and multiple linear regression analyses were performed to identify factors that may influence this phenotype of mitochondrial dysfunction. Results:In the MA cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and body mass index, CDR sum of boxes score, the APOE ɛ2/ɛ3 genotype, and education. Further, there was a significant relationship between cell-free mtDNA copy number and both education and CDR sum score. In the NHW cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and both age and CDR sum score. Age was associated with cell-free mtDNA in the NHW cohort. Conclusions:This evidence supports the existence of population-based differences in the factors that are predictive of this blood-based phenotype of mitochondrial dysfunction, which may be indicative of cognitive decline and AD risk.

Keywords: Alzheimer’s disease, cognitive decline, mitochondrial dysfunction, mtDNA

DOI: 10.3233/JAD-230880

Journal: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1407-1419, 2024