Circulating cell‐free DNA of mitochondrial origin connects cognitive and physical decline in aging and is associated with increased mortality: Molecular and cell biology/mitochondrial function/energetics. (7th December 2020)

• Record Type: Journal Article
• Authors: Nidadavolu, Lolita S.; Feger, Danielle M.; Gross, Alden L.; Bennett, David A.; Walston, Jeremy; Abadir, Peter; Oh, Esther S.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.045595
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Mitochondrial dysfunction and subsequently impaired energetics triggering cell death have been observed in both dementia and frailty. Cell death releases circulating cell‐free DNA (ccf‐DNA) from mitochondrial (ccf‐mtDNA) and nuclear (ccf‐nDNA) sources. Size and relative abundance of ccf‐mtDNA fragments is suggestive of mechanism of cell death; long ccf‐mtDNA fragments originate from cell necrosis and short ccf‐mtDNA fragments from apoptosis. Our hypothesis is that in aging there is common pathophysiology contributing to development of physical and cognitive decline and that ccf‐mtDNA are potential mediators of these changes. Method: Using ultra‐sensitive digital PCR, mitochondrial and nuclear ccf‐DNA was measured in serum from community‐dwelling individuals from the Rush Alzheimer's Disease Center Religious Orders Study/Rush Memory and Aging Project (median age 80.4, N = 670). Multiple regression analysis, adjusting for age, sex, race and education, associated ccf‐DNA with cognitive and physical measures, including neuropsychological testing and frailty including hand grip strength. Result: Higher levels of short ccf‐mtDNA fragments were associated with lower global cognitive scores, with a 0.09 decrease in global cognitive score per one copy increase in short fragment (p < 0.05). Higher levels of short ccf‐mtDNA normalized to serum ccf‐nDNA (ccf‐mtDNA/ccf‐nDNA) was associated with increased mortality (hazard ratio HR = 1.11) Longitudinal analysis demonstrated higher levels of long ccf‐mtDNA fragments at baseline was associated with greater frailty over time, with frailty score increasing 0.21 per year for every one copy increase in long fragment (p< 0.05). Cross‐sectional analysis demonstrated higher integrity ratio, defined as long ccf‐mtDNA relative to short ccf‐mtDNA, associated with increased handgrip strength (β= 0.14; 95% CI 0.01 – 0.26; p<0.05). Integrity ratio was associated with 0.14 increase in global cognition and 0.12 decrease in frailty score per increase in integrity ratio. Conclusion: Mitochondrial dysfunction is a primary theory of aging and we demonstrate that quantity and relative size of ccf‐mtDNA are associated with cognitive and physical trajectories over time. This study highlights the utility of ccf‐mtDNA fragments in identifying and risk stratifying older patients who are more likely to develop frailty and dementia. Further directions include identifying mechanisms by which ccf‐mtDNA fragments are generated and regulate downstream pathways.