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

Article type: Research Article

Authors: Tranah, Gregory J.^{a; *} | Nalls, Michael A.^b | Katzman, Shana M.^c | Yokoyama, Jennifer S.^d | Lam, Ernest T.^e | Zhao, Yiqiang^c | Mooney, Sean^c | Thomas, Fridtjof^f | Newman, Anne B.^g | Liu, Yongmei^h | Cummings, Steven R.^a | Harris, Tamara B.ⁱ | Yaffe, Kristine^j | The Health, Aging and Body Composition Study

Affiliations: [a] California Pacific Medical Center Research Institute, San Francisco, CA, USA | [b] Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA | [c] Buck Institute for Research on Aging, Novato, CA, USA | [d] Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA | [e] Institute for Human Genetics, University of California, San Francisco, CA, USA | [f] The University of Tennessee Health Science Center, Memphis, TN, USA | [g] Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA | [h] Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA | [i] Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, USA | [j] Departments of Psychiatry, Neurology, and Epidemiology, University of California, and the San Francisco VA Medical Center, San Francisco, CA, USA

Correspondence: [*] Correspondence to: Gregory J. Tranah, PhD, California Pacific Medical Center Research Institute, San Francisco Coordinating Center, UCSF, 185 Berry Street, Lobby 5, Suite 5700, San Francisco, CA 94107-1728, USA. E-mail: gtranah@sfcc-cpmc.edu.

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.

Keywords: Cognitive function, dementia, DNA sequencing, mitochondria, mtDNA, oxidative phosphorylation

DOI: 10.3233/JAD-2012-120466

Journal: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 357-372, 2012