title: Mitochondrial genomic analysis of late onset Alzheimer's disease reveals protective haplogroups H6A1A/H6A1B: the Cache County Study on Memory in Aging.
abstract: BACKGROUND
  Alzheimer's disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain.
  
  
  RESULTS
  We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p=0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status.
  
  
  CONCLUSIONS
  Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, USA.
authors.forename: Perry G
authors.initials: PG
authors.lastname: Ridge
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Maxwell
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Corcoran
authors.forename: Maria C
authors.initials: MC
authors.lastname: Norton
authors.forename: Joann T
authors.initials: JT
authors.lastname: Tschanz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: O'Brien
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kerber
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cawthon
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Munger
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology*; D004272:DNA, Mitochondrial / Q000235:genetics; D003710:Demography; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D054629:Genome, Mitochondrial / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008568:Memory; D012307:Risk Factors; D014589:Utah
chemical_list: D004272:DNA, Mitochondrial