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The distribution of cerebrovascular amyloid in Alzheimer’s disease varies with ApoE genotype

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Abstract

We performed a comparative study to assess cerebral amyloid angiopathy and ApoE genotype in cases of Alzheimer’s disease (AD). Ten ApoE 3,3 and ten ApoE 4,4 AD brains, as well as ten normal control brains, were selected after matching for age, sex, and duration of disease. Sections of middle frontal and inferior parietal cortex including white matter sections were stained with an antibody against amyloid beta (Aβ), and extensive analysis of arteriolar Aβ deposition was performed using digital image analysis. Quantification of the staining revealed a larger cross-section of arteriolar walls occupied by Aβ in ApoE 4,4 and ApoE 3,3 AD subjects compared to controls. Our results show Aβ deposition in gray matter and white matter arterioles was predominantly found in ApoE 4,4 brains and, overall, Aβ deposition was greatest in these cases. This observation implies that there is greater vascular amyloid deposition (particularly in the white matter arterioles) in ApoE 4,4 AD individuals compared to ApoE 3,3 AD. These observations may give insight into the etiology behind the increased risk for AD associated with the ApoE-ε4 allele and the pathogenesis of vascular Aβ deposition.

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References

  1. Alonzo NC, Hyman BT, Rebeck GW, Greenberg SM (1998) Progression of cerebral amyloid angiopathy: accumulation of amyloid-beta40 in affected vessels. J Neuropathol Exp Neurol 57:353–359

    PubMed  CAS  Google Scholar 

  2. Attems J, Jellinger KA (2004) Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol (Berl) 107:83–90

    Article  Google Scholar 

  3. Attems J, Lintner F, Jellinger KA (2004) Amyloid beta peptide 1–42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology. Acta Neuropathol (Berl) 107:283–291

    Article  CAS  Google Scholar 

  4. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403

    Article  PubMed  CAS  Google Scholar 

  5. Bock D (1973) Multivariate statistical methods in behavioral research. McGraw-Hill, New York City

    Google Scholar 

  6. Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 76:1501–1513

    Article  PubMed  CAS  Google Scholar 

  7. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239–259

    Article  CAS  Google Scholar 

  8. Buee L, Hof PR, Bouras C, Delacourte A, Perl DP, Morrison JH, Fillit HM (1994) Pathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathol (Berl) 87:469–480

    CAS  Google Scholar 

  9. Chalmers K, Wilcock GK, Love S (2003) APOE epsilon 4 influences the pathological phenotype of Alzheimer’s disease by favouring cerebrovascular over parenchymal accumulation of Abeta protein. Neuropathol Appl Neurobiol 29:231–238

    Article  PubMed  CAS  Google Scholar 

  10. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  PubMed  CAS  Google Scholar 

  11. Coria F, Moreno A, Rubio I, Garcia MA, Morato E, Mayor F Jr (1993) The cellular pathology associated with Alzheimer beta-amyloid deposits in non-demented aged individuals. Neuropathol Appl Neurobiol 19:261–268

    PubMed  CAS  Google Scholar 

  12. Coria F, Rubio I (1996) Cerebral amyloid angiopathies. Neuropathol Appl Neurobiol 22:216–227

    Article  PubMed  CAS  Google Scholar 

  13. DeMattos RB (2004) Apolipoprotein E dose-dependent modulation of beta-amyloid deposition in a transgenic mouse model of Alzheimer’s disease. J Mol Neurosci 23:255–262

    Article  PubMed  CAS  Google Scholar 

  14. Ellison D, Love S (2004) Neuropathology: a reference text of CNS pathology. Mosby Edinburgh, New York

    Google Scholar 

  15. Ervin JF, Pannell C, Szymanski M, Welsh-Bohmer K, Schmechel DE, Hulette CM (2004) Vascular smooth muscle actin is reduced in Alzheimer disease brain: a quantitative analysis. J Neuropathol Exp Neurol 63:735–741

    PubMed  CAS  Google Scholar 

  16. Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM (2005) Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci 25:2803–2810

    Article  PubMed  CAS  Google Scholar 

  17. German DC, Eisch AJ (2004) Mouse models of Alzheimer’s disease: insight into treatment. Rev Neurosci 15:353–369

    PubMed  Google Scholar 

  18. Hulette CM, Ervin JF, Pannell C, Schmechel DE, Strittmatter WJ, Sanders AM (2001) Vascular pathology in Alzheimer’s disease. Neurology 56:A182

    Article  Google Scholar 

  19. Hulette CM, Welsh-Bohmer KA, Murray MG, Saunders AM, Mash DC, McIntyre LM (1998) Neuropathological and neuropsychological changes in “normal” aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. J Neuropathol Exp Neurol 57:1168–1174

    PubMed  CAS  Google Scholar 

  20. Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097

    PubMed  CAS  Google Scholar 

  21. Koudinova NV, Berezov TT, Koudinov AR (1999) Beta-amyloid: Alzheimer’s disease and brain beta-amyloidoses. Biochemistry (Mosc) 64:752–757

    CAS  Google Scholar 

  22. Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240:622–630

    Article  PubMed  CAS  Google Scholar 

  23. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  24. Nicoll JA, Burnett C, Love S, Graham DI, Dewar D, Ironside JW, Stewart J, Vinters HV (1997) High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol 41:716–721

    Article  PubMed  CAS  Google Scholar 

  25. Nussbaum RL, Ellis CE (2003) Alzheimer’s disease and Parkinson’s disease. N Engl J Med 348:1356–1364

    Article  PubMed  CAS  Google Scholar 

  26. Olichney JM, Hansen LA, Hofstetter CR, Lee J-H, Katzman R, Thal LJ (2000) Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein e4. Arch Neurol 57:869–874

    Article  PubMed  CAS  Google Scholar 

  27. Premkumar DR, Cohen DL, Hedera P, Friedland RP, Kalaria RN (1996) Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer’s disease. Am J Pathol 148:2083–2095

    PubMed  CAS  Google Scholar 

  28. Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO (2003) Capillary and arterial cerebral amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29:106–117

    Article  PubMed  CAS  Google Scholar 

  29. Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11:575–580

    Article  PubMed  CAS  Google Scholar 

  30. Roses AD (1994) Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a secondary consequence dependent on APOE genotype and duration of disease. J Neuropathol Exp Neurol 53:429–437

    PubMed  CAS  Google Scholar 

  31. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472

    PubMed  CAS  Google Scholar 

  32. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:9649–9653

    Article  PubMed  CAS  Google Scholar 

  33. Stoll G, Meuller HW, Trapp BD, Griffin JW (1989) Oligodendrocytes but not astrocytes express apolipoprotein E after injury of rat optic nerve. Glia 2:170–176

    Article  PubMed  CAS  Google Scholar 

  34. Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293

    PubMed  Google Scholar 

  35. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD (2003) Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287–1301

    PubMed  Google Scholar 

  36. Tian J, Shi J, Bailey K, Lendon CL, Pickering-Brown SM, Mann DM (2004) Association between apolipoprotein E e4 allele and arteriosclerosis, cerebral amyloid angiopathy, and cerebral white matter damage in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75:696–699

    Article  PubMed  CAS  Google Scholar 

  37. Tian J, Shi J, Smallman R, Iwatsubo T, Mann DM (2006) Relationships in Alzheimer’s disease between the extent of Abeta deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen. Neuropathol Appl Neurobiol 32:332–340

    Article  PubMed  CAS  Google Scholar 

  38. Vinters HV (1987) Cerebral amyloid angiopathy. Acritical review. Stroke 18:311–324

    PubMed  CAS  Google Scholar 

  39. Yamada M (2004) Cerebral amyloid angiopathy and gene polymorphisms. J Neurol Sci 226:41–44

    Article  PubMed  CAS  Google Scholar 

  40. Zarow C, Zaias B, Lyness SA, Chui H (1999) Cerebral amyloid angiopathy in Alzheimer disease is associated with apolipoprotein E4 and cortical neuron loss. Alzheimer Dis Assoc Disord 13:1–8

    Article  PubMed  CAS  Google Scholar 

  41. Zhang WW, Lempessi H, Olsson Y (1998) Amyloid angiopathy of the human brain: immunohistochemical studies using markers for components of extracellular matrix, smooth muscle actin and endothelial cells. Acta Neuropathol (Berl) 96:558–563

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Dimitri Trembath

  2. Department of Medicine (Neurology), Duke University Medical Center, Durham, NC, USA

    John F. Ervin, Lucy Broom & Mari Szymanski

  3. Department of Psychiatry, Duke University Medical Center, Durham, NC, USA

    Kathleen Welsh-Bohmer

  4. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

    Carl Pieper

  5. Department of Pathology, Duke University Medical Center, Box 3712, Durham, NC, 27710, USA

    Christine M. Hulette

Authors
  1. Dimitri Trembath
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  2. John F. Ervin
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  3. Lucy Broom
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  4. Mari Szymanski
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  5. Kathleen Welsh-Bohmer
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  6. Carl Pieper
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  7. Christine M. Hulette
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Corresponding author

Correspondence to Christine M. Hulette.

Additional information

This study was supported by the National Institutes of Health NIA P50 AG05128 and P30 AG028377.

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Trembath, D., Ervin, J.F., Broom, L. et al. The distribution of cerebrovascular amyloid in Alzheimer’s disease varies with ApoE genotype. Acta Neuropathol 113, 23–31 (2007). https://doi.org/10.1007/s00401-006-0162-9

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  • DOI: https://doi.org/10.1007/s00401-006-0162-9

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