Human Genetics

, Volume 119, Issue 3, pp 241–254 | Cite as

Does the mitochondrial genome play a role in the etiology of Alzheimer’s disease?

  • Joanna L. Elson
  • Corinna Herrnstadt
  • Gwen Preston
  • Leon Thal
  • Christopher M. Morris
  • J. A. Edwardson
  • M. Flint Beal
  • Douglass M. Turnbull
  • Neil Howell
Original Investigation


We report here the analyses of complete mtDNA coding region sequences from more than 270 Alzheimer’s disease (AD) patients and normal controls to determine if inherited mtDNA mutations contribute to the etiology of AD. The AD patients and normal individuals were carefully screened and drawn from two populations of European descent in an effort to avoid spurious effects due to local population anomalies. Overall, there were no significant haplogroup associations in the combined AD and normal control sequence sets. Reduced median network analysis revealed that the AD mtDNA sequences contained a higher number of substitutions in tRNA genes, and that there was an elevated frequency of replacement substitutions in the complex I genes of the control sequences. Analysis of the replacement substitutions indicated that those arising in the AD mtDNAs were no more deleterious, on average, than those in the control mtDNAs. The only evidence for the synergistic action of mutations was the presence of both a rare non-conservative replacement substitution and a tRNA mutation in 2 AD mtDNAs, from a total of 145, whereas such a combination of mutations was not observed in the control sequences. Overall, the results reported here indicate that pathogenic inherited mtDNA mutations do not constitute a major etiological factor in sporadic AD. At most, a small proportion of AD patients carry a pathogenic mtDNA mutation and a small proportion of cognitively normal aged individuals carry a mtDNA mutation that reduces the risk of AD.

Supplementary material

439_2005_123_MOESM1_ESM.doc (104 kb)
Electronic supplementary material 1
439_2005_123_MOESM2_ESM.doc (600 kb)
Electronic supplementary material 2
439_2005_123_MOESM3_ESM.doc (200 kb)
Electronic supplementary material 3


  1. Anandatheerthavarada HK, Biswas G, Robin M-A, Avadhani NG (2003) Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 161:41–54PubMedCrossRefGoogle Scholar
  2. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147PubMedCrossRefGoogle Scholar
  3. Bandelt H-J, Forster P, Sykes BC, Richards MB (1995) Mitochondrial portraits of human populations using median networks. Genetics 141:743–753PubMedGoogle Scholar
  4. Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505PubMedCrossRefGoogle Scholar
  5. Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, Murri L, Rapoport SI, Solaini G (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATPase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 23:371–376PubMedCrossRefGoogle Scholar
  6. Brown MD, Yang C-C, Trounce I, Torroni A, Lott MT, Wallace DC (1992) A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I. Am J Hum Genet 51:378–385PubMedGoogle Scholar
  7. Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H, Yankner BA (2002) Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down’s syndrome. Neuron 33:677–688PubMedCrossRefGoogle Scholar
  8. Cardoso SM, Proenca MT, Santos S, Santana I, Oliveira CR (2004) Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging 25:105–110PubMedCrossRefGoogle Scholar
  9. Casley CS, Land JM, Sharpe MA, Clark JB, Duchen MR, Canevari L (2002) β amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis 10:258–267PubMedCrossRefGoogle Scholar
  10. Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, Obrenovich ME, Perry G, Smith MA (2002) Role of mitochondrial dysfunction in Alzheimer’s disease. J Neurosci Res 70:357–360PubMedCrossRefGoogle Scholar
  11. Chagnon P, Betard C, Robitaille Y, Cholette A, Gauvreau D (1995) Distribution of cytochrome oxidase activity in various neurodegenerative diseases. Mol Neurosci 6:711–715Google Scholar
  12. Chagnon P, Gee M, Filion M, Robitaille Y, Belouchi M, Gauvreau D (1999) Phylogenetic analyses of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French–Canadian founder population. Am J Med Genet 85:20–30PubMedCrossRefGoogle Scholar
  13. Chinnery PF, Johnson M, Taylor RW, Lightowlers RN, Turnbull DM (1997) A novel mitochondrial tRNA phenylalanine gene mutation presenting with acute rhabdomyolysis. Ann Neurol 41:408–410PubMedCrossRefGoogle Scholar
  14. Chinnery PF, Taylor GA, Howell N, Andrews RM, Morris CM, Taylor RW, McKeith IG, Perry RH, Edwardson JA, Turnbull DM (2000) Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies. Neurol 55:302–304Google Scholar
  15. Chinnery PF, Taylor GA, Howell N, Brown DT, Parsons TJ, Turnbull DM (2001) Point mutations of the mtDNA control region in normal and neurodegenerative human brains. Am J Hum Genet 68:529–532PubMedCrossRefGoogle Scholar
  16. Coskun PE, Beal MF, Wallace DC (2004) Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 101:10726–10731PubMedCrossRefGoogle Scholar
  17. Cottrell DA, Blakely EL, Johnson MA, Ince PG, Turnbull DM (2001) Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD. Neurology 57:260–264PubMedGoogle Scholar
  18. Cottrell DA, Borthwick GM, Johnson MA, Ince PG, Turnbull DM (2002) The role of cytochrome c oxidase deficient hippocampal neurons in Alzheimer’s disease. J Neuropath Appl Neurobiol 28:390–396CrossRefGoogle Scholar
  19. Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li Q-X, Barnham KJ, Curtain CC, Cherny RA, Cappai R, Dyrks T, Masters CL, Trounce IA (2005) Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-β1–42. J Neurosci 25:672–679PubMedCrossRefGoogle Scholar
  20. Danielson SR, Carelli V, Tan G, Martinuzzi A, Schapira AHV, Savontaus M-L, Cortopassi GA (2005) Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process. Brain 128:1026–1037PubMedCrossRefGoogle Scholar
  21. DiMauro S, Schon E (2001) Mitochondrial DNA mutations in human disease, Am J Med Genet 106:18–26PubMedCrossRefGoogle Scholar
  22. Elson JL, Turnbull DM, Howell N (2004) Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection. Am J Hum Genet 74:229–238PubMedCrossRefGoogle Scholar
  23. Ghosh SS, Swerdlow RH, Miller SW, Sheeman B, Parker WD, Davis RE (1999) Use of cytoplasmic hybrid lines for elucidating the role of mitochondrial dysfunction in Alzheimer’ disease and Parkinson’s disease. Ann NY Acad Sci 893:176–191PubMedCrossRefGoogle Scholar
  24. Gonnet GH, Cohen MA, Benner SA (1992) Exhaustive matching of the entire protein sequence database. Science 256:1443–1445PubMedCrossRefGoogle Scholar
  25. Herrnstadt C, Howell N (2004) An evolutionary perspective on pathogenic mtDNA mutations: haplogroup associations of clinical disorders. Mitochondrion 4:791–798PubMedCrossRefGoogle Scholar
  26. Herrnstadt C, Elson JL, Fahy E, Preston G, Turnbull DM, Anderson C, Ghosh SS, Olefsky JM, Beal MF, Davis RE, Howell N (2002) Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am J Hum Genet 70:1152–1171PubMedCrossRefGoogle Scholar
  27. Herrnstadt C, Preston G, Howell N (2003) Errors, phantom and otherwise, in human mtDNA sequences. Am J Hum Genet 72:1585–1586PubMedCrossRefGoogle Scholar
  28. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PLR, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023PubMedGoogle Scholar
  29. Howell N, Oostra R-J, Bolhuis PA, Spruijt L, Clarke LA, Mackey DA, Preston G, Herrnstadt C (2003a) Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 72:1460–1469CrossRefGoogle Scholar
  30. Howell N, Smejkal CB, Mackey DA, Chinnery PF, Turnbull DM, Herrnstadt C (2003b) The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates. Am J Hum Genet 72:659–670CrossRefGoogle Scholar
  31. Howell N, Elson JL, Chinnery PF, Turnbull DM (2005) mtDNA mutations and common neurodegenerative disorders. Trends Genet 21:583–584PubMedCrossRefGoogle Scholar
  32. Ioannidis JPA (2005) Why most published research findings are false. PloS Med 2:e124PubMedCrossRefGoogle Scholar
  33. Ito S, Ohta S, Nishimaki K, Kagawa Y, Soma R, Kuno S, Komatsuzaki Y, Mizusawa H, Hayashi J-I (1999) Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from elderly patients with Alzheimer’s disease. Proc Natl Acad Sci USA 96:2099–2103PubMedCrossRefGoogle Scholar
  34. Keers SM, Gibson AM, Turnbull DM, Chinnery PF (2004) No evidence of an association between the mtDNA 16184-93 polyC tract and late onset dementia. J Med Genet 41:957–958CrossRefGoogle Scholar
  35. Khan SM, Cassarino DS, Abramova NN, Keeney PM, Borland MK, Trimmer PA, Krebs CT, Bennett JC, Parks JK, Swerdlow RH, Parker WD, Bennett JP (2000) Alzheimer’s disease cybrids replicate β-amyloid abnormalities through cell death pathways. Ann Neurol 48:148–155PubMedCrossRefGoogle Scholar
  36. Kish SJ, Bergeran C, Rajput A, Dozie S, Mastrogiacomo F, Chang LJ, Wilson JM, DiStefano LM, Nobrega JN (1992) Brain cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 59:776–779PubMedCrossRefGoogle Scholar
  37. Kish SJ, Mastrogiacomo F, Guttman M, Furukawa Y, Taanman J-W, Dozic S, Pandolfo M, Lamarche J, DiStefano L, Chang L-J (1999) Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer’s disease and in hereditary spincerebellar ataxia disorders: a nonspecific change? J Neurochem 72:700–707PubMedCrossRefGoogle Scholar
  38. Kondrashov FA (2005) Prediction of pathogenic mutations in mitochondrially encoded human tRNAs. Hum Mol Genet 14:2415–2419PubMedCrossRefGoogle Scholar
  39. Lehtonen MS, Moilanen JS, Majamaa K (2003) Increased variation in mtDNA in patients with familial sensorineural hearing impairment. Hum Genet 113:220–227PubMedCrossRefGoogle Scholar
  40. Lin MT, Simon DK, Ahn CG, Kim LM, Beal MF (2002) High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 11:133–145PubMedCrossRefGoogle Scholar
  41. Maurer I, Zierz S, Moller H-J (2000) A selective defect of cytochrome c oxidase is present in brain of Alzheimer’s disease patients. Neurobiol Aging 21:455–462PubMedCrossRefGoogle Scholar
  42. Mayeux R (2003) Epidemiology of neurodegeneration. Ann Rev Neurosci 26:81–104PubMedCrossRefGoogle Scholar
  43. McFarland R, Elson JL, Taylow RW, Howell N, Turnbull DM (2004a) Assigning pathogenicity to mitochondrial tRNA mutations: when “definitely maybe” is not good enough. Trends Genet 20:591–596CrossRefGoogle Scholar
  44. McFarland R, Taylor RW, Chinnery PF, Howell N, Turnbull DM (2004b) A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis. Neuromuscul Disord 14:162–166CrossRefGoogle Scholar
  45. Moilanen JS, Majamaa K (2003) Phylogenetic network and physiochemical properties of nonsynonymous mutations in the protein-coding genes of human mitochondrial DNA. Mol Biol Evol 20:1195–1210PubMedCrossRefGoogle Scholar
  46. Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63:2179–2184PubMedCrossRefGoogle Scholar
  47. Niemi A-K, Hervonen A, Hurme M, Karhunen PJ, Jylhä M, Majamaa K (2003) Mitochondrial DNA polymorphisms associated with longevity in a Finnish population. Hum Genet 112:29–33PubMedCrossRefGoogle Scholar
  48. Ng PC, Henkoff JG, Henikoff S (2000) PHAT: a transmembrane-specific substitution matrix. Bioinformatics 16:760–766PubMedCrossRefGoogle Scholar
  49. Parker WD, Parks JK (2005) Mitochondrial ND5 mutations in idiopathic Parkinson’s disease. Biochem Biophys Res Commun 326:667–669PubMedCrossRefGoogle Scholar
  50. Parker WD, Filley CM, Parks JK (1990) Cytochrome oxidase deficiency in Alzheimer’s disease. Neurol 40:1302–1303Google Scholar
  51. Parker WD, Parks JK, Filley CM, Kleinschmidt-Demasters BK (1994) Electron transport chain defects in Alzheimer’s disease brain. Neurol 44:1090–1096Google Scholar
  52. Persson B, Argos P (1994) Prediction of transmembrane segments in proteins utilizing multiple sequence alignments. J Mol Biol 237:182–192PubMedCrossRefGoogle Scholar
  53. Richards M, Macaulay V, Hickey E, Vega E, Sykes B, Guida V, Rengo C, Sellitto D, Cruciani F, Kivisild T, Villems R, Thomas M, Rychkov S, Rychkov O, Rychkov Y, Golge M, Dimitrov D, Hill E, Bradley D, Romano V, Cali F, Vona G, Demaine A, Papiha S, Triantaphyidis C, Stefanescu G, Hatina J, Belledi M, Di renzo A, Novelletto A, Oppenheim A, Norby S, Al-Zaheri N, Santachiara-Benerecetti S, Scozzari R, Torroni A, Bandelt H-J (2000) Tracing European founder lineages in the Near Eastern mtDNA pool. Am J Hum Genet 67:1251–1277PubMedGoogle Scholar
  54. Rose G, Passarino G, Carrieri G, Altomare K, Greco V, Bertolini S, Bonafe M, Franceschi C, De Benedictis G (2001) Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians. Eur J Hum Genet 9:701–707PubMedCrossRefGoogle Scholar
  55. Roubertoux PL, Sluyter F, Carlier M, Marcet B, Maarouf-Veray F, Cherif C, Marcian C, Arrechi P, Godin F, Jamon M, Verrier B, Cohen-Salmon C (2003) Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet 35:65–69PubMedCrossRefGoogle Scholar
  56. Schon EA, Manfredi G (2003) Neuronal degeneration and mitochondrial dysfunction. J Clin Invest 111:303–312PubMedGoogle Scholar
  57. Schon EA, Shoubridge EA, Moraes CT (1998) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 51:326–327PubMedGoogle Scholar
  58. Simonian NA, Hyman BT (1993) Functional alterations in Alzheimer’s disease: diminution of cytochrome oxidase in the hippocampal formation. J Neuropath Exp Neurol 52:580–585PubMedCrossRefGoogle Scholar
  59. Simonian NA, Hyman BT (1994) Functional alterations in Alzheimer’s disease: selective loss of mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation. J Neuropath Exp Neurol 53:508–512PubMedCrossRefGoogle Scholar
  60. Smith MA, Drew KL, Nunomara A, Takeda A, Hirai K, Zhu X, Atwood CS, Raina AK, Rottkamp CA, Sayre LM, Friedland RP, Perry G (2002) Amyloid-β, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem Int 40:527–531PubMedCrossRefGoogle Scholar
  61. Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JPJ, Davis RE, Parker WD (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49:918–925PubMedGoogle Scholar
  62. Thomas PD, Kejariwal A (2004) Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. Proc Natl Acad Sci USA 101:15398–15403PubMedCrossRefGoogle Scholar
  63. Trimmer PA, Swerdlow RH Parks JK, Keeney P, Bennett JP, Miller SW, Davis RE, Parker WD (2000) Abnormal mitochondrial morphology in sporadic Parkinson’s and Alzheimer’s disease cybrid cell lines. Exp Neurol 162:37–50PubMedCrossRefGoogle Scholar
  64. Trimmer PA, Keeney PM, Borland MK, Simon FA, Almeida J, Swerdlow R, Parks JP, Parker WD, Bennett JP (2004) Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer’s disease worsen with passage in culture. Neurobiol Dis 15:29–39PubMedCrossRefGoogle Scholar
  65. Valla J, Berndt JD, Gonzalez-Lima F (2001) Energy hypometabolism in posterior cingulate cortex of Alzheimer’s patients: superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 21:4923–4930PubMedGoogle Scholar
  66. Vilmi T, Moilanen JS, Finnila S, Majamaa K (2005) Sequence variation in the tRNA genes of human mitochondrial DNA. J Mol Evol 60:587–597PubMedCrossRefGoogle Scholar
  67. van der Walt JM, Dementieva YA, Martin ER, Scott WK, Nicodemus KK, Kroner CC, Welsh-Bohmer KA, Saunders AM, Roses AD, Small GW, Schmechel DE, Doraisamy PM, Gilbert JR, Haines JL, Vance JM, Pericak-Vance MA (2004) Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 365:28–32PubMedCrossRefGoogle Scholar
  68. Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3:219–226PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Joanna L. Elson
    • 1
  • Corinna Herrnstadt
    • 2
  • Gwen Preston
    • 2
  • Leon Thal
    • 3
  • Christopher M. Morris
    • 4
  • J. A. Edwardson
    • 4
  • M. Flint Beal
    • 5
  • Douglass M. Turnbull
    • 1
    • 6
  • Neil Howell
    • 7
    • 8
  1. 1.Mitochondrial Research Group, School of Neurology, Neurobiology, and PsychiatryThe University of Newcastle upon TyneNewcastle upon TyneUnited Kingdom
  2. 2.MitoKor Inc. (now MIGENIX Corp.)San DiegoUSA
  3. 3.Department of NeurosciencesUniversity of California San DiegoSan DiegoUSA
  4. 4.Institute for the Health of the Elderly, Newcastle General HospitalNewcastle upon TyneUnited Kingdom
  5. 5.Department of NeurologyCornell University Medical CollegeNew YorkUSA
  6. 6.MRC/University of Newcastle upon Tyne Development Centre for Clinical Brain AgeingNewcastle upon TyneUnited Kingdom
  7. 7.MIGENIX Corp.San DiegoUSA
  8. 8.Department of Radiation OncologyThe University of Texas Medical BranchGalvestonUSA

Personalised recommendations