Translational Stroke Research

, Volume 3, Supplement 1, pp 102–112

TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer’s Disease

  • Valerie Valant
  • Brendan T. Keenan
  • Christopher D. Anderson
  • Joshua M. Shulman
  • William J. Devan
  • Alison M. Ayres
  • Kristin Schwab
  • Joshua N. Goldstein
  • Anand Viswanathan
  • Steven M. Greenberg
  • David A. Bennett
  • Philip L. De Jager
  • Jonathan Rosand
  • Alessandro Biffi
  • the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Original Article

Abstract

Cerebral amyloid angiopathy (CAA) related intracerebral hemorrhage (ICH) is a devastating form of stroke with no known therapies. Clinical, neuropathological, and genetic studies have suggested both overlap and divergence between the pathogenesis of CAA and the biologically related condition of Alzheimer’s disease (AD). Among the genetic loci associated with AD are APOE and TOMM40, a gene in close proximity to APOE. We investigate here whether variants within TOMM40 are associated with CAA-related ICH and CAA neuropathology. Using cohorts from the Massachusetts General Hospital (MGH) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we designed a comparative analysis of high-density SNP genotype data for CAA-related ICH and AD. APOE ε4 was associated with CAA-related ICH and AD, while APOE ε2 was protective in AD but a risk factor for CAA. A total of 14 SNPs within TOMM40 were associated with AD (p < 0.05 after multiple testing correction), but not CAA-related ICH (all p > 0.20); as a result, all AD-associated SNPs within TOMM40 showed heterogeneity of effect in CAA-related ICH (BD p < 0.001). Analysis of CAA neuropathology in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), however, found that neuritic plaque, diffuse plaque burden, and vascular amyloid burden associated with all TOMM40 SNPs (p < 0.02). These results suggest that alterations in TOMM40 can promote vascular as well as plaque amyloid deposition, but not the full pathogenic pathway leading to CAA-related ICH.

Keywords

TOMM40 APOE Cerebral amyloid angiopathy Alzheimer’s disease Linkage disequilibrium 

Supplementary material

12975_2012_161_MOESM1_ESM.doc (92 kb)
ESM 1(DOC 92 kb)

References

  1. 1.
    Vinters HV, Gilbery JJ. Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke. 1983;14:924–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Ellis RJ, Olichney JM, Thal LJ, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology. 1996;46:1592–6. Google Scholar
  3. 3.
    Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450–60.PubMedCrossRefGoogle Scholar
  4. 4.
    Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701.PubMedCrossRefGoogle Scholar
  5. 5.
    Vinters HV. Cerebral amyloid angiopathy: a microvascular link between parenchymal and vascular dementia? Ann Neurol. 2001;49:691–3.PubMedCrossRefGoogle Scholar
  6. 6.
    Greenberg SM, Gurol ME, Rosand J, Smith EE. Amyloid angiopathy-related vascular cognitive impairment. Stroke. 2004;35:2616–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76.PubMedCrossRefGoogle Scholar
  8. 8.
    O’Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342:240–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Biffi A, Haplin A, Towfighi A, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology. 2010;75:693–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Greenberg SM, Vonsattel JP. Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke. 1997;28(7):1418–22.PubMedCrossRefGoogle Scholar
  11. 11.
    Ellis RJ, Olichney JM, Thal LJ, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology. 1996;46:1592–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Bekris LM, Yu CE, Bird TD, et al. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;23:213–27.PubMedCrossRefGoogle Scholar
  13. 13.
    Revesz T, Holton JL, Lashley T, et al. Genetics and molecular pathologenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol. 2009;118:115–30.PubMedCrossRefGoogle Scholar
  14. 14.
    Biffi A, Sonni A, Anderson CD, et al. Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann Neurol. 2010;68(6):934–43.PubMedCrossRefGoogle Scholar
  15. 15.
    Naj AC, Jun G, Beecham GW, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011;43(5):436–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Hollingworth P, Harold D, Sims R, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43(5):429–35.PubMedCrossRefGoogle Scholar
  17. 17.
    Hong MG, Alexeyenko A, Lambert JC, et al. Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer’s disease. J Hum Genet. 2010;55(10):707–9.Google Scholar
  18. 18.
    Roses AD. An inherited variable Poly-T repeat genotype in TOMM40 in Alzheimer’s disease. Arch Neurol. 2010;67(5):536–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet. 2011;377(9770):1019–31.PubMedCrossRefGoogle Scholar
  20. 20.
    Revesz T, Ghiso J, Lashley T, et al. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol. 2003;62(9):885–98.PubMedGoogle Scholar
  21. 21.
    Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol. 2011;10(3):241–52.PubMedCrossRefGoogle Scholar
  22. 22.
    Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001;56(4):537–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Petersen RC, Aisen PS, Beckett LA, et al. Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010;74(3):201–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412–4.PubMedCrossRefGoogle Scholar
  25. 25.
    Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98.PubMedCrossRefGoogle Scholar
  26. 26.
    Arvanitakis Z, Leurgans SE, Wang Z, et al. Cerebral amyloid angiopathy pathology and cognitive decline in older persons. Ann Neurol. 2011;69:320–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Bennett DA, Schneider JA, Buchman AS, et al. The Rush Memory and Aging Project: study design and baseline characteristics of the study cohort. Neuroepidemiology. 2005;25:163–75.PubMedCrossRefGoogle Scholar
  28. 28.
    McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s disease. Neurology. 1984;34:939–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Bennett DA, Wilson RS, Schneider JA, et al. Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology. 2003;60:246–52.PubMedCrossRefGoogle Scholar
  30. 30.
    Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging. 1997;18(4 Suppl):S1-2. Google Scholar
  31. 31.
    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.PubMedCrossRefGoogle Scholar
  32. 32.
    Mirra SS, Heyman A, McKeel D, et al. The consortium to establish a registry for Alzheimer’s disease (cerad). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology. 1991;41:479–86.PubMedCrossRefGoogle Scholar
  33. 33.
    Olichney JM, Hansen LA, Hofstetter CR, et al. Cerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol. 1995;52:702–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Nakata-Kudo Y, Mizuna T, Yamada K, et al. Microbleeds in Alzheimer disease are more related to cerebral amyloid angiopathy than cerebrovascular disease. Dement Geriatr Cogn Disord. 2006;22:8–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Mandybur TI. The incidence of cerebral amyloid angiopahy in Alzheimer’s disease. Neurology. 1975;25:120–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Attems J, Jellinger KA. Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol. 2004;107:83–90.PubMedCrossRefGoogle Scholar
  37. 37.
    Bennett DA, Schneider JA, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology. 2006;66:1837–44.PubMedCrossRefGoogle Scholar
  38. 38.
    Biffi A, Shulman JM, Jagiella JM, et al. Genetic variation at CR1 increases risk of cerebral amyloid angiopathy. Neurology. 2012;78:1–8.CrossRefGoogle Scholar
  39. 39.
    Biffi A, Anderson CD, Desikan RS, et al. Genetic variation and neuroimaging measures in Alzheimer’s disease. Arch Neruol. 2010;67(6):677–85.CrossRefGoogle Scholar
  40. 40.
    Potkin SG, Guffanti G, Lakatos A, et al. Alzheimer’s Disease Neuroimaging Initiative. Hippocampal atrophy as a quantitative trait in genome-wide association study indentifying novel susceptibility genes for Alzheimer’s disease. PLoS One. 2009;4(8):e6501.PubMedCrossRefGoogle Scholar
  41. 41.
    Purcell SM, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.PubMedCrossRefGoogle Scholar
  42. 42.
    Breslow NE, Day NE. Statistical methods in cancer research. Volume I—the analysis of case–control studies. IARC Sci Publ. 1980;32:5–338.PubMedGoogle Scholar
  43. 43.
    Samarasekera N, Smith C, Al-Shahi Salman R. The association between cerebral amyloid angiopathy and intracerebral haemorrhage: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2012;83:275–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Greenberg SM, Vonsattel JP, Segal AZ, et al. Association of apolipoprotein E epsilon2 and vasculopathy in cerebral amyloid angiopathy. Neurology. 1998;50(4):961–5.PubMedCrossRefGoogle Scholar
  45. 45.
    McCarron MO, Nicoll JA, Stewart J, et al. The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage. J Neuropathol Exp Neurol. 1999;58(7):711–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Grossman I, Lutz MW, Crenshaw DG, et al. Alzheimer’s disease: diagnostics, prognosis and the road to prevention. EPMA J. 2010;1(2):293–303.PubMedCrossRefGoogle Scholar
  47. 47.
    Herculano-Houzel S. Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution. PLoS One. 2011;6(3):e17514.PubMedCrossRefGoogle Scholar
  48. 48.
    Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430(7000):631–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Hansson-Petersen CA, Alikhani N, Behbahani H, et al. The amyloid β-peptide is imported into mitochondrial via the TOM import machinery and localized to mitochondrial cristae. PNAS. 2008;105(35):13145–50.PubMedCrossRefGoogle Scholar
  50. 50.
    Purcell SM, Cherny SS, Sham PC. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19(1):149–50.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Valerie Valant
    • 1
    • 2
    • 3
    • 4
  • Brendan T. Keenan
    • 4
    • 5
  • Christopher D. Anderson
    • 1
    • 2
    • 3
    • 4
  • Joshua M. Shulman
    • 4
    • 5
  • William J. Devan
    • 1
    • 2
    • 3
    • 4
  • Alison M. Ayres
    • 3
  • Kristin Schwab
    • 3
  • Joshua N. Goldstein
    • 1
    • 3
    • 6
  • Anand Viswanathan
    • 3
  • Steven M. Greenberg
    • 3
  • David A. Bennett
    • 7
  • Philip L. De Jager
    • 4
    • 5
  • Jonathan Rosand
    • 1
    • 2
    • 3
    • 4
  • Alessandro Biffi
    • 1
    • 2
    • 3
    • 4
  • the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
  1. 1.Division of Neurocritical Care and Emergency Neurology, Department of NeurologyMassachusetts General HospitalBostonUSA
  2. 2.Center for Human Genetic ResearchMassachusetts General HospitalBostonUSA
  3. 3.Hemorrhagic Stroke Research GroupMassachusetts General HospitalBostonUSA
  4. 4.Program in Medical and Population GeneticsBroad InstituteCambridgeUSA
  5. 5.Program in Translational NeuroPsychiatric Genomics, Institute for Neurosciences, Departments of Neurology and PsychiatryBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  6. 6.Department of Emergency MedicineMassachusetts General HospitalBostonUSA
  7. 7.Rush Alzheimer’s Disease Center, Department of Neurological ScienceRush University medical CenterChicagoUSA

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