Mitochondrial DNA Sequence Variation Associated with Dementia and Cognitive Function in the Elderly

California Pacific Medical Center Research Institute, San Francisco, CA, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 07/2012; 32(2):357-72. DOI: 10.3233/JAD-2012-120466
Source: PubMed


Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increased neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10-12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia (OR = 1.86, 95% CI = 1.23, 2.82, p = 0.0008) and haplogroup J participants experienced a statistically significant 8-year decline in 3MS (β = -0.14, 95% CI = -0.27, -0.03, p = 0.0006), both compared with common haplogroup H. The m.15244A>G, p.G166G, CytB variant was associated with a significant decline in DSST score (β = -0.58, 95% CI -0.89, -0.28, p = 0.00019) and the m.14178T>C, p.I166V, ND6 variant was associated with a significant decline in 3MS score (β = -0.87, 95% CI -1.31, -3.86, p = 0.00012). Finally, we sequenced the complete ~16.5 kb mtDNA from 135 Health ABC participants and identified several highly conserved and potentially functional nonsynonymous variants unique to 22 dementia cases and aggregate sequence variation across the hypervariable 2-3 regions that influences 3MS and DSST scores.

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Available from: Jennifer S Yokoyama, Aug 27, 2014
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    • "As the prevalence of AD reaches epidemic proportions in the United States and worldwide in the coming decades (Hebert et al., 2003), understanding the basis of cognitive impairment is critical to treating and preventing disease. In the present study, we extend our previous mtDNA work in the Health, Aging, and Body Composition (Health ABC) Study (Tranah et al., 2012b) by assessing dementia risk and cognitive decline in elderly African Americans, and by examining whether mtDNA variation is associated with circulating Ab levels and markers of oxidative stress (plasma oxidized LDL and urinary 8-iso-prostaglandin F 2a ). We have shown that greater energy expenditure is associated with a reduced incidence of cognitive impairment in older adults from the Health ABC Study (Middleton et al., 2011) and have documented significant differences in metabolic rate among African and European mitochondrial haplogroups from this study (Tranah et al., 2011, 2012a). "
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    ABSTRACT: Mitochondrial dysfunction occurs early in the course of several neurodegenerative diseases, and is potentially related to increased oxidative damage and amyloid-beta (Abeta) formation in Alzheimer's disease. The goals of this study were to assess mtDNA sequence associations with dementia risk, 10-year cognitive change, and markers of oxidative stress and Abeta among 1089 African-Americans in the population-based Health, Aging, and Body Composition Study. Participants were free of dementia at baseline, and incidence was determined in 187 (18%) cases over 10 to 12 follow-up years. Haplogroup L1 participants were at increased risk for developing dementia (odds ratio = 1.88, 95% confidence interval = 1.23-2.88, p = 0.004), lower plasma Abeta42 levels (p = 0.03), and greater 10-year decline on the Digit Symbol Substitution Test (p = 0.04) when compared with common haplogroup L3. The p.V193I, ND2 substitution was associated with significantly higher Abeta42 levels (p = 0.0012), and this association was present in haplogroup L3 (p = 0.018) but not L1 (p = 0.90) participants. All associations were independent of potential confounders, including APOEepsilon4 status and nuclear genetic ancestry. Identification of mtDNA sequence variation associated with dementia risk and cognitive decline may contribute to the development of new treatment targets and diagnostic tests that identify responders to interventions targeting mitochondria.
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    ABSTRACT: Mitochondrial DNA (mtDNA) is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the "missing heritability" of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases.
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