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Association of apolipoprotein ɛ4 allele and neuropathologic findings in patients with dementia

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Abstract

Apolipoprotein E (APOE) is a lipoprotein expressed in liver and brain as one of three isoforms (APOE 2, APOE 3 and APOE 4). Recent findings suggest that the presence of APOE 4 is associated with an increased risk for both familial Alzheimer's disease and late-onset Alzheimer's disease. We extended these observations by determining the frequency of APOE alleles in patients with pathologically confirmed Alzheimer's Disease (AD), Parkinson's disease (PD), diffuse Lewy Body disease (DLBD), AD with concomitant PD pathology, demented PD patients without or with concomitant AD pathology and in schizophrenics with a progressive dementia (SCHIZ+DEM). The APOE genotype was determined by restriction digestion of polymerase chain reaction-amplified DNA isolated from frozen brain samples. The frequency of the APOE ɛ4 allele was highest among sporadic AD and DLBD patients (0.30 and 0.38, respectively) and lowest in the SCHIZ+DEM and non-demented PD patients (0.06 and 0.1, respectively). Thus, the APOE ɛ4 allele is over-represented selectively in patients with dementias associated with plaques and tangles and/or cortical Lewy bodies, but not in demented schizophrenics or non-demented PD patients.

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References

  1. American Psychiatric Association (1987) the diagnostic and statistical manual of mental disorders, 3rd edn. American Psychiatric Press, Washington, DC

    Google Scholar 

  2. Amouyel P, Cottel D, Berr C, Vidal O, Brousseau T (1994) ɛ4 allele of the apolipoprotein gene is a potent risk factor for cognitive impairment. Abstracts of the 4th International Conference on Alzheimer's disease Pergamon Press, New York, abstr. no. 177

    Google Scholar 

  3. Arai H, Schmidt ML, Lee VM-Y, Hurtig HL, Adler CH, Greenberg B, Trojanowski JQ (1992) Epitode analysis of senile plaque components in the hippocampus of patients with Parkinson's disease. Neurology 42:1315–1322

    Google Scholar 

  4. Ausebel MF, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (eds) (1992) Current protocols in molecular biology. Wiley, New York

    Google Scholar 

  5. Benjamin R, Leake A, Edwardson JA, McKeith IG, Ince PG, Perry RH, Morris CM (1994) Apolipoprotein E genes in Lewy body and Parkinson's disease. Lancet 343: 1565

    Google Scholar 

  6. Bouthillier D, Sing CF, Davignon J (1983) Apolipoprotein E phenotyping with a single gel method-application to the study of informative mating. J Lipid Res 24: 1060–1966

    Google Scholar 

  7. 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

    Google Scholar 

  8. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer's disease. Nature Genet 7: 180–184

    Google Scholar 

  9. Das HK, McPherson J, Brun GAP, Karathanasis SK, Breslow JL (1985) Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene. J Biol Chem 260: 6240–6247

    Google Scholar 

  10. Dikson DW, Schmidt ML, Lee VM-Y, Zhao M-L, Yen S-H, Trojanowski JQ (1994) Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. Acta Neuropathol 87: 269–276

    Google Scholar 

  11. Galasko D, Saitoh T, Xia Y, Thal LJ, Katzman R, Hill LR, Hansen L (1994) The apolipoprotein E allele ɛ4 is overrepresented in patients with the Lewy body variant of Alzheimer's disease. Neurology 44: 1950–1951

    Google Scholar 

  12. Gibb WR, Esiri MM, Lees AJ (1985) Clinical and pathological features of diffuse cortical Lewy body disease (Lewy body dementia). Brain 110: 1131–1153

    Google Scholar 

  13. Govoni S, Frisoni GB, Calabresi L, Geroldi C, Bianchetti M, Trabucchi G, Franceschini G (1994) Apolipoprotein ɛ4 allele frequency in non-Alzheimer's dementias. Abstracts of the 4th International Conference on Alzheimer's disease. Pergamon Press, New York, abstr. no. 179

    Google Scholar 

  14. Hansen LA, Masliah E, Galasko D, Terry RD (1993) Plaqueonly Alzheimer disease is usually the Lewy body variant and vice-versa. J Neuropathol Exp Neurol 52: 648–654

    Google Scholar 

  15. Harrington CR, Louwagie J, Rossau R, Vanmechelen E, Perry RH, Perry EK, Xuereb JH, Roth M, Wischik CM (1994) Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Am J Pathol 145: 1472–1475

    Google Scholar 

  16. Hill WD, Lee VM-Y, Hurtig HI, Murray JM, Trojanowski JQ (1991) Epitopes located in spatially separated domains of each neurofilament subunit are present in the Lewy bodies of Parkinson's disease. J Comp Neurol 109: 150–160

    Google Scholar 

  17. Hill WD, Cohen JA, Arai M, Trojanowski JQ (1993) Neurofilament protein mRNA is reduced in Parkinson's disease substantia nigra pars compacta neurons. J Comp Neurol 329: 328–336

    Google Scholar 

  18. Hixson EJ, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I. J Lipid Res 31: 545–548

    Google Scholar 

  19. Koller WC, Glatt SL, Hubble JP, Paolo A, Tröster AI, Handler MS, Horvat RS, Martin C, Schmidt K, Karst A, Wijsman EM, Yu C-E, Schellenberg GD (1995) Apolipoprotein E genotypes in Parkinson's disease with and without dementia. Ann Neurol 37: 242–245

    Google Scholar 

  20. Lippa CF, Smith TW, Saunders AM, Crook R, Salo-Pulaski D, Davies P, Hardy J, Roses AD, Dickson D (1994) Apolipoprotein E genotype and Lewy body disease. Neurology 45: 97–103

    Google Scholar 

  21. Ma J, Yee A, Brewer HB Jr, Das S, Potter H (1994) Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments. Nature 372: 92–94

    Google Scholar 

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

    Google Scholar 

  23. Marden K, Maestre G, Cote L, Mejja H, Alfaro B, Halim A, Tang M, Tycko B, Mayeux R (1994) The apolipoprotein ɛ4 allele in Parkinson's disease with and without dementia. Neurology 44: 1330–1331

    Google Scholar 

  24. Mayeux R, Stern Y, Ottman R, Tatemichi TK, Tang MX, Maestre G (1993) The apolipoprotein ɛ4 allele in patients with Alzheimer's disease. Ann Neurol 34: 752–754

    Google Scholar 

  25. Muramatsu T, Higuchi S, Arai H, Sasaki H, Yamada K, Hayashida M, Trojanowski JQ (1995) Apolipoprotein ɛ4 allele distribution in alcoholic dementia and Alzheimer's disease in Japan. Ann Neurol (in press)

  26. Myers RH, Schaefer EJ, Wilson PWF, D'Agostino R, Bachman DL, Ordovas JM, Aul R, Cobb JL, Wolf PA (1994) Apolipoprotein E allele 4 is associated with dementia in the Framingham study. Abstracts of the 4th International Conference on Alzheimer's disease. Pergamon Press, New York, abstr. no. 299

    Google Scholar 

  27. Nalbantoglu J, Gilfix BM, Bertrand P, Robitaille Y, Gauthier S, Rosenblant DS, Poirier J (1994) Predictive value of apolipoprotein E genotyping in Alzheimer's disease: results of an autopsy series and an analysis of several combined studies. Ann Neurol 36: 889–895

    Google Scholar 

  28. Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposit and neurofibrillary tangles in Alzheimer's disease and kuru plaques amyloid in Creutzfeldt-Jacob disease. Brain Res 541: 163–166

    Google Scholar 

  29. Pericak-Vance MA, Bebout JL, Gaskell PC, Yamaoka LA, Hung W-Y, Alberts MJ, Walker AP, et al (1991) Linkage studies in familiar Alzheimer's disease: evidence for chromosome 19 linkage. Am J Hum Genet 48: 1034–1054

    Google Scholar 

  30. Pickeing-Brown SM, Mann DMA, Brouke JP, Roberts DA, Balderson D, Burns A, Byrne J, Owen F (1994) Apolipoprotein E4 and Alzheimer's disease pathology in Lewy body disease and in other β-amyloid-forming diseases. Lancet 343: 1155

    Google Scholar 

  31. Pickering-Brown S, Roberts D, Owen F (1994) Apolipoprotein E4 alleles and non-Alzheimer's disease forms of dementia. Neurodegeneration 5: 95–96

    Google Scholar 

  32. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993) Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342: 697–699

    Google Scholar 

  33. Pollanen MS, Dickdon DW, Bergeron C (1993) Pathology and biology of the Lewy Body. J Neuropathol Exp Neurol 52: 183–191

    Google Scholar 

  34. 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 ɛ4 with late-onset familiar and sporadic Alzheimer's disease. Neurology 43: 1467–1472

    Google Scholar 

  35. Saunders AM, Schmader K, Breitner JCS, Benson MD, Brown WT, Goldfarb L, Goldgaber D, Manwarning MD, Szymanski MH, McCown N, Dole KC, Schmechel DE, Strittmater WJ, Pericak-Vance MA, Roses AD (1993) Apolipoprotein Eɛ4 allele distribution in late-onset Alzheimer's disease and in other amyloid-forming disease. Lancet 342: 710–711

    Google Scholar 

  36. S-PLUS (1991) User's Manual, vol 2, version 3. Statistical Sciences Press, Seattle

    Google Scholar 

  37. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in lateonset Alzheimer's disease. Proc Natl Acad Sci USA 90: 8649–8653

    Google Scholar 

  38. Schmidt ML, Murray JM, Lee VM-Y, Hill DW, Wertkin A, Trojanowski JQ (1991) Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol 139: 53–65

    Google Scholar 

  39. St Clair D, Norman J, Perry R, Yates C, Wilcock G, Brookes A (1994) Apolipoprotein E ɛ4 allele frequency in patients with Lewy body dementia, Alzheimer's disease and age-matched controls. Neurosci Lett 176: 45–46

    Google Scholar 

  40. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familiar Alzheimer diseas. Proc Natl Acad Sci USA 90: 1977–1981

    Google Scholar 

  41. Strittmatter WJ, Weisgraber KH, Huang DY, Dong L-M, Salversen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD (1993) Binding of human apolipoprotein E to synthetic β peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90: 8099–8102

    Google Scholar 

  42. Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong L-M, Jakes R, Huang DY, Pericak-Vance M, Schmechel D, Roses AD (1994) Isoforms-specific interactions of apolipoprotein E with microtubule-associated protein tau; implication for Alzheimer disease. Proc Natl Acad Sci USA 91: 11183–11186

    Google Scholar 

  43. Trojanowski JQ, Schmidt ML, Shin R-W, Bramblett GT, Rao D, Lee VM-Y (1993) Altered Tau and neurofilaments protein in neurodegenerative diseases: diagnostic implications for Alzheimer's disease and Lewy body dementias. Brain Pathol 3: 45–54

    Google Scholar 

  44. van Duijn CM, de Knijff P, Cruts M, Wehnert A, Havekes LM, Hofman A, Van Broeckhoven C (1994) Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease. Nature Genet 7: 74–78

    Google Scholar 

  45. Weisgraber KH, Rall SC Jr, Mahley RW (1981) Human E apolipoprotein heterogenity: cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem 256: 9077–9081

    Google Scholar 

  46. Wisniewski T, Frangione B (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 135: 235–238

    Google Scholar 

  47. Yu C-E, Payami H, Olson JM, Boehnke M, Wijsman EM, Orr HT, et al (1994) The apolipoprotein E/CI/CII gene cluster and late on-onset Alzheimer disease. Am J Hum Genet 54: 631–642

    Google Scholar 

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Authors and Affiliations

  1. Centre for Research in Neuroscience, Montréal General Hospital, McGill University, H3G 1A4, Montréal, Québec, Canada

    M. -G. Martinoli & J. -P. Julien

  2. Departments of Human Genetics Medicine, and Pediatrics, McGill University, H3G 1A4, Montréal, Québec, Canada

    T. M. Fujiwara

  3. Department of Pathology and Laboratory Medicine, The University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA

    J. Q. Trojanowski, M. L. Schmidt & V. M. -Y. Lee

  4. Department of Neurology, The University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA

    J. Q. Trojanowski, S. E. Arnold & V. M. -Y. Lee

  5. Department of Psychiatry, The University of Pennsylvania School of Medicine, 19105, Philadelphia, PA, USA

    S. E. Arnold, H. Hurtig & C. Clark

  6. Department of Neurology, The Graduate Hospital, 19146, Philadelphia, PA, USA

    H. Hurtig & C. Clark

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  1. M. -G. Martinoli
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  8. J. -P. Julien
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Correspondence to M. -G. Martinoli.

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Martinoli, M.G., Trojanowski, J.Q., Schmidt, M.L. et al. Association of apolipoprotein ɛ4 allele and neuropathologic findings in patients with dementia. Acta Neuropathol 90, 239–243 (1995). https://doi.org/10.1007/BF00296506

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  • DOI: https://doi.org/10.1007/BF00296506

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