Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly

Gregory J. Tranah, Michael A. Nalls, Shana M. Katzman, Jennifer S. Yokoyama, Ernest T. Lam, Yiqiang Zhao, Sean Mooney, Fridtjof Thomas, Anne B. Newman, Yongmei Liu, Steven R. Cummings, Tamara B. Harris, Kristine Yaffe

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)357-372
Number of pages16
JournalJournal of Alzheimer's Disease
Volume32
Issue number2
DOIs
StatePublished - Jan 1 2012

Fingerprint

Mitochondrial DNA
Cognition
Dementia
Body Composition
Alzheimer Disease
Hospital Records
Health
DNA Damage
Incidence
Wounds and Injuries
Population

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Tranah, G. J., Nalls, M. A., Katzman, S. M., Yokoyama, J. S., Lam, E. T., Zhao, Y., ... Yaffe, K. (2012). Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly. Journal of Alzheimer's Disease, 32(2), 357-372. https://doi.org/10.3233/JAD-2012-120466

Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly. / Tranah, Gregory J.; Nalls, Michael A.; Katzman, Shana M.; Yokoyama, Jennifer S.; Lam, Ernest T.; Zhao, Yiqiang; Mooney, Sean; Thomas, Fridtjof; Newman, Anne B.; Liu, Yongmei; Cummings, Steven R.; Harris, Tamara B.; Yaffe, Kristine.

In: Journal of Alzheimer's Disease, Vol. 32, No. 2, 01.01.2012, p. 357-372.

Research output: Contribution to journalArticle

Tranah, GJ, Nalls, MA, Katzman, SM, Yokoyama, JS, Lam, ET, Zhao, Y, Mooney, S, Thomas, F, Newman, AB, Liu, Y, Cummings, SR, Harris, TB & Yaffe, K 2012, 'Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly', Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 357-372. https://doi.org/10.3233/JAD-2012-120466
Tranah, Gregory J. ; Nalls, Michael A. ; Katzman, Shana M. ; Yokoyama, Jennifer S. ; Lam, Ernest T. ; Zhao, Yiqiang ; Mooney, Sean ; Thomas, Fridtjof ; Newman, Anne B. ; Liu, Yongmei ; Cummings, Steven R. ; Harris, Tamara B. ; Yaffe, Kristine. / Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly. In: Journal of Alzheimer's Disease. 2012 ; Vol. 32, No. 2. pp. 357-372.
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