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. 1993 Oct 15;90(20):9649–9653. doi: 10.1073/pnas.90.20.9649

Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.

D E Schmechel 1, A M Saunders 1, W J Strittmatter 1, B J Crain 1, C M Hulette 1, S H Joo 1, M A Pericak-Vance 1, D Goldgaber 1, A D Roses 1
PMCID: PMC47627  PMID: 8415756

Abstract

Amyloid beta-peptide (A beta) deposition in senile plaques and cerebral vessels is a neuropathological feature of Alzheimer disease (AD). We examined the possibility that commonly observed variability in A beta deposition in late-onset AD might be related to apolipoprotein E genotype (APOE gene; the two most common alleles are 3 and 4), since APOE4 is a susceptibility gene for late-onset AD and apolipoprotein E interacts strongly with A beta in vitro. In an autopsy series of brains of late-onset AD patients, we found a strong association of APOE4 allele with increased vascular and plaque A beta deposits. Late-onset AD patients with one or two APOE4 alleles have a distinct neuropathological phenotype compared with patients homozygous for APOE3.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allsop D., Landon M., Kidd M., Lowe J. S., Reynolds G. P., Gardner A. Monoclonal antibodies raised against a subsequence of senile plaque core protein react with plaque cores, plaque periphery and cerebrovascular amyloid in Alzheimer's disease. Neurosci Lett. 1986 Jul 24;68(2):252–256. doi: 10.1016/0304-3940(86)90152-7. [DOI] [PubMed] [Google Scholar]
  2. Chartier-Harlin M. C., Crawford F., Houlden H., Warren A., Hughes D., Fidani L., Goate A., Rossor M., Roques P., Hardy J. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991 Oct 31;353(6347):844–846. doi: 10.1038/353844a0. [DOI] [PubMed] [Google Scholar]
  3. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., Pericak-Vance M. A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
  4. DeKosky S. T., Scheff S. W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990 May;27(5):457–464. doi: 10.1002/ana.410270502. [DOI] [PubMed] [Google Scholar]
  5. Diedrich J. F., Minnigan H., Carp R. I., Whitaker J. N., Race R., Frey W., 2nd, Haase A. T. Neuropathological changes in scrapie and Alzheimer's disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes. J Virol. 1991 Sep;65(9):4759–4768. doi: 10.1128/jvi.65.9.4759-4768.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gelman B. B., Goodrum J., Bouldin T. W. Macrophage apolipoprotein synthesis and endoneurial distribution as a response to segmental demyelination. J Neuropathol Exp Neurol. 1991 Jul;50(4):383–407. doi: 10.1097/00005072-199107000-00001. [DOI] [PubMed] [Google Scholar]
  7. Glenner G. G. Amyloidosis. Its role in Alzheimer's disease and other diseases. Ann Pathol. 1981;1(2):105–108. [PubMed] [Google Scholar]
  8. Goate A., Chartier-Harlin M. C., Mullan M., Brown J., Crawford F., Fidani L., Giuffra L., Haynes A., Irving N., James L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704–706. doi: 10.1038/349704a0. [DOI] [PubMed] [Google Scholar]
  9. Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., Gajdusek D. C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987 Feb 20;235(4791):877–880. doi: 10.1126/science.3810169. [DOI] [PubMed] [Google Scholar]
  10. Hendriks L., van Duijn C. M., Cras P., Cruts M., Van Hul W., van Harskamp F., Warren A., McInnis M. G., Antonarakis S. E., Martin J. J. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992 Jun;1(3):218–221. doi: 10.1038/ng0692-218. [DOI] [PubMed] [Google Scholar]
  11. Hixson J. E., Vernier D. T. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990 Mar;31(3):545–548. [PubMed] [Google Scholar]
  12. Hyman B. T., Tanzi R. E., Marzloff K., Barbour R., Schenk D. Kunitz protease inhibitor-containing amyloid beta protein precursor immunoreactivity in Alzheimer's disease. J Neuropathol Exp Neurol. 1992 Jan;51(1):76–83. doi: 10.1097/00005072-199201000-00009. [DOI] [PubMed] [Google Scholar]
  13. Ikeda S., Allsop D., Glenner G. G. A study of the morphology and distribution of amyloid beta protein immunoreactive plaque and related lesions in the brains of Alzheimer's disease and adult Down's syndrome. Prog Clin Biol Res. 1989;317:313–323. [PubMed] [Google Scholar]
  14. Joachim C. L., Morris J. H., Selkoe D. J. Clinically diagnosed Alzheimer's disease: autopsy results in 150 cases. Ann Neurol. 1988 Jul;24(1):50–56. doi: 10.1002/ana.410240110. [DOI] [PubMed] [Google Scholar]
  15. Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., Multhaup G., Beyreuther K., Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19;325(6106):733–736. doi: 10.1038/325733a0. [DOI] [PubMed] [Google Scholar]
  16. Khachaturian Z. S. Diagnosis of Alzheimer's disease. Arch Neurol. 1985 Nov;42(11):1097–1105. doi: 10.1001/archneur.1985.04060100083029. [DOI] [PubMed] [Google Scholar]
  17. Mandybur T. I. The incidence of cerebral amyloid angiopathy in Alzheimer's disease. Neurology. 1975 Feb;25(2):120–126. doi: 10.1212/wnl.25.2.120. [DOI] [PubMed] [Google Scholar]
  18. Mirra S. S., Heyman A., McKeel D., Sumi S. M., Crain B. J., Brownlee L. M., Vogel F. S., Hughes J. P., van Belle G., Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991 Apr;41(4):479–486. doi: 10.1212/wnl.41.4.479. [DOI] [PubMed] [Google Scholar]
  19. Mullan M., Crawford F., Axelman K., Houlden H., Lilius L., Winblad B., Lannfelt L. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992 Aug;1(5):345–347. doi: 10.1038/ng0892-345. [DOI] [PubMed] [Google Scholar]
  20. Murakami M., Ushio Y., Morino Y., Ohta T., Matsukado Y. Immunohistochemical localization of apolipoprotein E in human glial neoplasms. J Clin Invest. 1988 Jul;82(1):177–188. doi: 10.1172/JCI113568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Murrell J., Farlow M., Ghetti B., Benson M. D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science. 1991 Oct 4;254(5028):97–99. doi: 10.1126/science.1925564. [DOI] [PubMed] [Google Scholar]
  22. Namba Y., Tomonaga M., Kawasaki H., Otomo E., Ikeda K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991 Feb 8;541(1):163–166. doi: 10.1016/0006-8993(91)91092-f. [DOI] [PubMed] [Google Scholar]
  23. Oltersdorf T., Fritz L. C., Schenk D. B., Lieberburg I., Johnson-Wood K. L., Beattie E. C., Ward P. J., Blacher R. W., Dovey H. F., Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144–147. doi: 10.1038/341144a0. [DOI] [PubMed] [Google Scholar]
  24. Pericak-Vance M. A., Bebout J. L., Gaskell P. C., Jr, Yamaoka L. H., Hung W. Y., Alberts M. J., Walker A. P., Bartlett R. J., Haynes C. A., Welsh K. A. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet. 1991 Jun;48(6):1034–1050. [PMC free article] [PubMed] [Google Scholar]
  25. Pericak-Vance M. A., Yamaoka L. H., Haynes C. S., Speer M. C., Haines J. L., Gaskell P. C., Hung W. Y., Clark C. M., Heyman A. L., Trofatter J. A. Genetic linkage studies in Alzheimer's disease families. Exp Neurol. 1988 Dec;102(3):271–279. doi: 10.1016/0014-4886(88)90220-8. [DOI] [PubMed] [Google Scholar]
  26. Saunders A. M., Strittmatter W. J., Schmechel D., George-Hyslop P. H., Pericak-Vance M. A., Joo S. H., Rosi B. L., Gusella J. F., Crapper-MacLachlan D. R., Alberts M. J. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993 Aug;43(8):1467–1472. doi: 10.1212/wnl.43.8.1467. [DOI] [PubMed] [Google Scholar]
  27. Selkoe D. J., Bell D. S., Podlisny M. B., Price D. L., Cork L. C. Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease. Science. 1987 Feb 20;235(4791):873–877. doi: 10.1126/science.3544219. [DOI] [PubMed] [Google Scholar]
  28. Strittmatter W. J., Saunders A. M., Schmechel D., Pericak-Vance M., Enghild J., Salvesen G. S., Roses A. D. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977–1981. doi: 10.1073/pnas.90.5.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Strittmatter W. J., Weisgraber K. H., Huang D. Y., Dong L. M., Salvesen G. S., Pericak-Vance M., Schmechel D., Saunders A. M., Goldgaber D., Roses A. D. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8098–8102. doi: 10.1073/pnas.90.17.8098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A., St George-Hyslop P., Van Keuren M. L., Patterson D., Pagan S., Kurnit D. M., Neve R. L. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):880–884. doi: 10.1126/science.2949367. [DOI] [PubMed] [Google Scholar]
  31. Terry R. D., Masliah E., Salmon D. P., Butters N., DeTeresa R., Hill R., Hansen L. A., Katzman R. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4):572–580. doi: 10.1002/ana.410300410. [DOI] [PubMed] [Google Scholar]
  32. Vallet P. G., Guntern R., Hof P. R., Golaz J., Delacourte A., Robakis N. K., Bouras C. A comparative study of histological and immunohistochemical methods for neurofibrillary tangles and senile plaques in Alzheimer's disease. Acta Neuropathol. 1992;83(2):170–178. doi: 10.1007/BF00308476. [DOI] [PubMed] [Google Scholar]
  33. Van Nostrand W. E., Wagner S. L., Suzuki M., Choi B. H., Farrow J. S., Geddes J. W., Cotman C. W., Cunningham D. D. Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. Nature. 1989 Oct 12;341(6242):546–549. doi: 10.1038/341546a0. [DOI] [PubMed] [Google Scholar]
  34. Wenham P. R., Price W. H., Blandell G. Apolipoprotein E genotyping by one-stage PCR. Lancet. 1991 May 11;337(8750):1158–1159. doi: 10.1016/0140-6736(91)92823-k. [DOI] [PubMed] [Google Scholar]
  35. Wisniewski T., Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett. 1992 Feb 3;135(2):235–238. doi: 10.1016/0304-3940(92)90444-c. [DOI] [PubMed] [Google Scholar]
  36. Wisniewski T., Golabek A., Matsubara E., Ghiso J., Frangione B. Apolipoprotein E: binding to soluble Alzheimer's beta-amyloid. Biochem Biophys Res Commun. 1993 Apr 30;192(2):359–365. doi: 10.1006/bbrc.1993.1423. [DOI] [PubMed] [Google Scholar]

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