title: Mitochondrial DNA sequence associations with dementia and amyloid-β in elderly African Americans.
abstract: Mitochondrial dysfunction occurs early in the course of several neurodegenerative diseases, and is potentially related to increased oxidative damage and amyloid-β (Aβ) 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 Aβ 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 Aβ42 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 Aβ42 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 APOEε4 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.
authors.affiliation: California Pacific Medical Center Research Institute-San Francisco, San Francisco, CA, USA. Electronic address: gtranah@sfcc-cpmc.edu.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.forename: Shana M
authors.initials: SM
authors.lastname: Katzman
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesari
authors.forename: Todd M
authors.initials: TM
authors.lastname: Manini
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Kristine
authors.initials: K
authors.lastname: Yaffe
mesh_terms: D001741:Black or African American; D000368:Aged; D016229:Amyloid beta-Peptides / Q000097:blood*; D001483:Base Sequence / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D003071:Cognition / Q000502:physiology; D015331:Cohort Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D003704:Dementia / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D018384:Oxidative Stress / Q000235:genetics*; D010446:Peptide Fragments / Q000097:blood*; D011446:Prospective Studies; D012306:Risk; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D004272:DNA, Mitochondrial; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Amyloid-β; Dementia; Mitochondria; Oxidative stress; mtDNA