Apolipoprotein E4 and Alzheimer's disease in São Paulo - Brazil

Almeida, Osvaldo P.; Shimokomaki, Carlos M.

doi:10.1590/S0004-282X1997000100001

Abstracts

Several recently published studies showed the existence of an association between the allele ε4 of the apolipoprotein E and Alzheimer's disease (AD) in developed countries. We examined this association in 55 patients with possible or probable AD and 56 elderly controls referred to outpatient clinics at the "Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo" and "Centro de Saúde Escola da Faculdade de Saúde Pública da Universidade de São Paulo". The allele ε4 was significantly more frequent among patients than controls (20.9% vs 8.9%, p=0.038). Thirty-six percent of the cases presented with at least one allele ε4 compared with only 17.9% of the controls (p=0.027). The presence of at least one ε4 allele increased by 2.63 times the risk of subjects being diagnosed as suffering from AD. All three ε4ε4 patients were male and had a pre-senile onset of the disease. There was no significant difference between senile and pre-senile cases (41.9% vs 29.2%, p=0.326) nor between men and women (36.0% vs 36.7%, p=0.959) regarding their risk of being ε4. The age at onset of symptoms did not differ among the different genotype groups, although ε4ε4 cases showed a consistent trend for earlier onset. When only patients with the diagnosis of "probable AD" were included in the analysis (n=43), we observed that 22.1% of the alleles were e4, a rate that was significantly higher than the 8.9% of controls (p=0.024). This study supports the association between the presence of the ε4 allele and AD and extend this finding to Brazilian patients. Nonetheless, the presence of this allele is not necessary nor sufficient for the development of the disease and it is possible that its contribution to the pathogenesis of the disorder depends on the subject's ethnic group.

dementia; Alzheimer's disease; risk factors; apolipoprotein E; ApoE4

Vários estudos publicados durante os últimos dois anos demonstraram a existência de uma forte associação entre o alelo ε4 da apolipoproteina E e a doença de Alzheimer (AD) em países do hemisfério norte. Este estudo investigou a associação entre a presença do alelo ε4 da apolipoproteina E e a doença de Alzheimer em amostra de pacientes brasileiros atendidos em um serviço público de saúde. Foram investigados 55 pacientes com diagnóstico de AD possível ou provável e 56 controles idosos atendidos em serviços ambulatoriais do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e do Centro de Saúde Escola da Faculdade de Saúde Pública da Universidade de São Paulo. A determinação do tipo de alelo foi feita através de tipagem genética. Do total de alelos investigados (n=222) observou-se um excesso de ε4 entre os pacientes (20,9% vs 8,9%, p=0,038), com 36,4% deles exibindo ao menos 1 alelo ε4 (vs 17,9% dos controles, p=0,027). O risco de indivíduos com ao menos 1 alelo ε4 serem diagnosticados como sofrendo de AD foi 2,63 vezes maior que para aqueles sem este alelo. Três pacientes apresentaram o genótipo ε4ε4, sendo todos homens com início pré-senil da doença. Não se observou diferença na freqüência de ao menos 1 alelo ε4 entre pacientes com demência senil e pré-senil (41,9% vs 29,2%, p=0,326) ou entre homens e mulheres (36,0% vs 36,7%, p=0,959). Não havia diferença significativa quanto à idade de início dos sintomas entre grupos de pacientes com diferentes genótipos, embora indivíduos com genótipo ε4ε4 revelassem tendência a desenvolver a doença mais precocemente. Quando apenas pacientes com diagnóstico de AD provável foram incluídos na análise (n=43), verificou-se que 22,1% dos alelos eram ε4, uma taxa significativamente maior que os 8,9% dos controles (p=0,024). Os resultados deste estudo confirmam a associação entre ε4 e AD e estendem este achado para uma amostra de pacientes brasileiros. Entretanto, a presença desse alelo não é necessária nem suficiente para o desenvolvimento da doença e é possível que sua contribuição varie de acordo com o grupamento étnico ao qual pertence o indivíduo.

demência; doença de Alzheimer; fatores de risco; apolipoproteína E; ApoE4

Apolipoprotein E4 and Alzheimer's disease in São Paulo - Brazil

Apolipoproteina E 4 e doença de Alzheimer em São Paulo - Brasil

Osvaldo P. Almeida^I; Carlos M. Shimokomaki^II

^IDepartamento de Psiquiatria da Faculdade de Medicina da Universidade de São Paulo (USP)

^IILaboratório de Genética do Instituto de Biologia da USP

ABSTRACT

Several recently published studies showed the existence of an association between the allele ε4 of the apolipoprotein E and Alzheimer's disease (AD) in developed countries. We examined this association in 55 patients with possible or probable AD and 56 elderly controls referred to outpatient clinics at the "Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo" and "Centro de Saúde Escola da Faculdade de Saúde Pública da Universidade de São Paulo". The allele ε4 was significantly more frequent among patients than controls (20.9% vs 8.9%, p=0.038). Thirty-six percent of the cases presented with at least one allele ε4 compared with only 17.9% of the controls (p=0.027). The presence of at least one ε4 allele increased by 2.63 times the risk of subjects being diagnosed as suffering from AD. All three ε4ε4 patients were male and had a pre-senile onset of the disease. There was no significant difference between senile and pre-senile cases (41.9% vs 29.2%, p=0.326) nor between men and women (36.0% vs 36.7%, p=0.959) regarding their risk of being ε4. The age at onset of symptoms did not differ among the different genotype groups, although ε4ε4 cases showed a consistent trend for earlier onset. When only patients with the diagnosis of "probable AD" were included in the analysis (n=43), we observed that 22.1% of the alleles were e4, a rate that was significantly higher than the 8.9% of controls (p=0.024). This study supports the association between the presence of the ε4 allele and AD and extend this finding to Brazilian patients. Nonetheless, the presence of this allele is not necessary nor sufficient for the development of the disease and it is possible that its contribution to the pathogenesis of the disorder depends on the subject's ethnic group.

Key words: dementia, Alzheimer's disease, risk factors, apolipoprotein E, ApoE4.

RESUMO

Vários estudos publicados durante os últimos dois anos demonstraram a existência de uma forte associação entre o alelo ε4 da apolipoproteina E e a doença de Alzheimer (AD) em países do hemisfério norte. Este estudo investigou a associação entre a presença do alelo ε4 da apolipoproteina E e a doença de Alzheimer em amostra de pacientes brasileiros atendidos em um serviço público de saúde. Foram investigados 55 pacientes com diagnóstico de AD possível ou provável e 56 controles idosos atendidos em serviços ambulatoriais do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e do Centro de Saúde Escola da Faculdade de Saúde Pública da Universidade de São Paulo. A determinação do tipo de alelo foi feita através de tipagem genética. Do total de alelos investigados (n=222) observou-se um excesso de ε4 entre os pacientes (20,9% vs 8,9%, p=0,038), com 36,4% deles exibindo ao menos 1 alelo ε4 (vs 17,9% dos controles, p=0,027). O risco de indivíduos com ao menos 1 alelo ε4 serem diagnosticados como sofrendo de AD foi 2,63 vezes maior que para aqueles sem este alelo. Três pacientes apresentaram o genótipo ε4ε4, sendo todos homens com início pré-senil da doença. Não se observou diferença na freqüência de ao menos 1 alelo ε4 entre pacientes com demência senil e pré-senil (41,9% vs 29,2%, p=0,326) ou entre homens e mulheres (36,0% vs 36,7%, p=0,959). Não havia diferença significativa quanto à idade de início dos sintomas entre grupos de pacientes com diferentes genótipos, embora indivíduos com genótipo ε4ε4 revelassem tendência a desenvolver a doença mais precocemente. Quando apenas pacientes com diagnóstico de AD provável foram incluídos na análise (n=43), verificou-se que 22,1% dos alelos eram ε4, uma taxa significativamente maior que os 8,9% dos controles (p=0,024). Os resultados deste estudo confirmam a associação entre ε4 e AD e estendem este achado para uma amostra de pacientes brasileiros. Entretanto, a presença desse alelo não é necessária nem suficiente para o desenvolvimento da doença e é possível que sua contribuição varie de acordo com o grupamento étnico ao qual pertence o indivíduo.

Palavras-chave: demência, doença de Alzheimer, fatores de risco, apolipoproteína E, ApoE4.

Full text available only in PDF format.

Texto completo disponível apenas em PDF.

Acknowledgements

This study was supported by a grant from FAPESP (94/2158-8) and CNPq. OPA is supported by CNPq. We are grateful to Luciana Vasquez, Prof. Dr. Maria Rita Passos Bueno and Prof. Dr. Mayana Zatz for helping with the molecular analysis of the blood samples; Prof. Dr. Ricardo Nitrini, the staff at the Neurology Outpatient Clinic and at PROTER for helping with the recruitment of patients, and the staff at the "Centro de Saúde Escola da FSP-USP" for helping with the selection of controls.

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6. Chartier-Harlin MC, Crawford P, Houlden H et al. Early onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor gene. Nature 1991 ;353:844-846.

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9. Corder EH, Saunders AM, Strittmatter WJ et al. The apolipoprotein E E4 allele and sex-specific risk of Alzheimer's disease. J Am Med Assoc 1995:273:373-374.

10. Evans DA, Funkenstein H, Albert MS et al. Prevalence of Alzheimer's disease in a community population of older persons. J Am Med Assoc 1989:262:2551-2556.

11. Feskens EJM.Havekes LM. KalmijnS.Knijff P.Launer LJ, Kromhout D. Apolipoprotein ε4 allele and cognitive decline in elderly men. Brit Med J 1994; 309:1202-1206.

12. Förstl H, Czech C, Sattel H et al. Apolipoprotein E und Alzheimer-Demenz. Nervenarzt 1994;65:780-786.

13. Goate A, Chartier-Halin MC, Mullan M et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1992,349:704-706.

14. Guo C, Marynen P, Cassiman JJ. A rapid, semiautomated method for apolipoprotein E genotyping. PCR Meth Applicat 1993;2:348-350.

15. Hardy J A, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. TiPS 1991:12:383-388.

16. Hendrie HC, Hall KS, Hui S et al. Apolipoprotein E genotypes and Azlheimer's disease in a community study of elderly African Americans. Ann Neurol 1995:37:118-120.

17. Jones CT, Morris S, Yates CM et al. Mutation in codon 713 of the β-amyloid precursor protein gene presenting with schizophrenia. Nature Genet 1992:1:306-309.

18. Kawamata J, Tanaka S, Shimohama S, Ueda K, Kimura J. Apolipoprotein E polymorphism in Japanese patientes with Alzheimer's disease or vascular dementia J Neurol Neurosurg Psychiatry 1994;57:1414-1416.

19. Kuusisto J, Koivisto K, Kervinen K et al. Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study. Br Med J 1994;309:636-638.

20. Levy-Lahad E, Wasco W, Poorkaj P et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 1995;269:973-977.

21. Levy-Lahad E, Wijsman EM, Nemens E et al. A familial Alzheimer's disease locus on chromosome 1. Science 1995;269: 970-973.

22. Li J, Ma J, Potter H. Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3. Proc Nat Acad Sci USA 1995;92:12180-12184.

23. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622-630.

24. McKhann G, Drachman D, Folstein M, Katzman R Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS/ADRDA workgroup under the auspices of the department of Health and Human services task force on Azheimer's disease. Neurology 1984;34:939-944.

25. McLoughlin DM, Lovestone S. Alzheimer's disease: recent advances in molecular pathology and genetics. Int J Geriatr Psychiatry 1994;9:431-444.

26. Mullan M, Houlden H, Windelspecht M et al. A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α1-antichymotrypsin gene. Nature Genet 1992; 2:340-342.

27. Muramatsu T, Higuchi S, Arai H et al. Apolipoprotein E ε4 allele distribution in alcoholic dementia and in Alzheimer's disease in Japan. Ann Neurol 1994; 36:797-799.

28. Muriel J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 1991;254:97-99.

29. Orrell M, Sahakian B. Education and dementia: research evidence supports the concept "use or loose it". Br Med J 1995;310: 951-952.

30. Ott A, Breteler MMB, van Harskamp F et aL Prevalence of Alzheimer's disease and vascular dementia: association with educationthe Rotterdam study. Br Med J 1995;310:970-973.

31. Payami H, Montee KR, Kaye JA et al Alzheimer's disease, apolipoprotein E4, and gender. J Am Med Assoc 1994;271: 1316-1317.

32. Pericak-Vance MA, Bebout JL, Gaskell PC Jr. et al Linkage studies in familial Alzheimer's disease: evidence for chromosome 19 linkage. Am J Hum Genet 1991 ;48:1034-1050.

33. Poirier J. Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. TiNS 1994;17:525-530.

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

35. Rebeck GW, Perls TT, West HL, Sodhi P, Lipsitz LA, Hyman BT. Reduced apolipoprotein ε4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals. Neurology 1994,44:1513-1516.

36. ReedT, Carmelli D, Swan GE et al. Lower cognitive performance in normal older adult male twins carrying the apolipoprotein Eε4 allele. Arch Neurol 1994.51:1189-1192.

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39. Roses AD, Strittmatter WJ, Pericak-Vance M, Corder EH, Saunders AM, Schmechel DE. Clinical application of apolipoprotein E genotyping to Alzheimer's disease. Lancet 1994;343:1564-1565.

40. Saunders AM, Strittmatter WJ, Schmechel D et al. Association of apolipoprotein E allele e4 with late onset familial and sporadic Alzheimer's disease. Neurology 1993;43:1467-1472.

41. Schachter F, Faure-Delanef L, Guenot F et al. Genetic associations with human longevity at the ApoE and ACE loci. Nature Genet 1994,6:29-33.

42. Schmechel DE, Saunders AM, Strittmatter WJ et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Nat Acad Sci USA 1993;90:9649-9653.

43. Selkoe DJ. Alzheimer's disease: a central role for amyloid. J Neuropathol Exp Neurol 1994;53:438-447.

44. Sherrington R, Rogaev EI, Liang Y et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995;375:754-760.

45. Small GW, Mazziotta JC, Collins MT et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. J Am Med Assoc 1995;273:942-947.

46. St. George-Hyslop P, McLachlan DC, Tuda T, Rogaev E. Alzheimer's disease and possible gene interaction. Science 1994:263: 537.

47. Stern Y, Alexander GE, Prohovnik I, Mayeux R. Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer's disease. Ann Neurol 1992,32:371-375.

48. Strittmatter WJ. In: Meeting Briefs - Neuroscientists reach a critical mass in Washington. Science 1993;262:1210-1211.

49. Strittmatter WJ, Saunders AM, Schmechel D et al. Apoplipoprotein E: high avidity binding to the β-amyloid and increased frequency of type 4 allele in late onset familial Alzheimer's disease. Proc Nat Acad Sci USA 1993;90:1977-1981.

50. Strittmatter WJ, Weisgraber H, Huang DY et al. Binding of human apoplipoprotein E to synthetic amyloid β peptide: isoform-specific effects and implications for late onset Alzheimer disease. Proc Nat Acad Sci USA 1993,90:8098-8102.

51. Thompson P, Blessed G. Correlation between the 37 item Mental Test Score and abbreviated 10-item Mental Test Score by psychogeriatric day patients. Br J Psychiatry 1987;151:206-209.

52. Tsai MS, Tangalos EG, Petersen RC et al. Apolipoprotein E: risk factor for Alzheime disease. Am J Hum Genet 1994;54: 643-649.

53. Utermann G. The apolipoprotein E connection. Curr Biol 1994;4:362-365.

54. Van Duijn CM, Stijnen T, Hofman A. Risk factors for Alzheimer's disease: overview of the EURODEM collaborative re-analysis of case-control studies. Int J Epidemiol 1991 ;20: S4-S12.

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Aceite: 15-outubro-1996

Dr. Osvaldo P. Almeida - Unidade de Idosos (UNID), Departamento de Saúde Mental, Faculdade de Ciências Médicas da Santa Casa de São Paulo - Rua Dr. Cesário Motta Jr 112 - 01277-000 São Paulo SP - Brasil. E-mail: Oswalm@ibm.net

1. Alzheimer A. "Über eine eigenartige Erkrankung der Hirnrinde" 1907. Translated by Jarvik L, Greenson H, About a peculiar disease of the cerebral cortex. Alzh Dis Assoc Disord 1987;1: 7-8.
2.. Alzheimer A."Über eigenartige Krankheitsfalle des späteren Alters" 1911. Translated by Förstl H, Levy R. On certain peculiar diseases of old age. Hist Psychiatry 1991 ;2:71-101.
4. Bachman DL, Wolf PA, Linn R et al. Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham study. Neurology 1992,42:115-119.
5. Boyles JK, Zoellner CD, Anderson LJ et al. A role for apolipoprotein E, apolipoprotein A-l, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of rat sciatic nerve. J Clin Invest 1989:83:1015-1031.
6. Chartier-Harlin MC, Crawford P, Houlden H et al. Early onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor gene. Nature 1991 ;353:844-846.
7. Clark RF, Goate AM. Molecular genetics of Alzheimer's disease. Arch Neurol 1993:50:1164-1172.
8. Corder EH, Saunders AM, Strittmatter WJ et al. Gene doses of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993:261:921-923.
9. Corder EH, Saunders AM, Strittmatter WJ et al. The apolipoprotein E E4 allele and sex-specific risk of Alzheimer's disease. J Am Med Assoc 1995:273:373-374.
10. Evans DA, Funkenstein H, Albert MS et al. Prevalence of Alzheimer's disease in a community population of older persons. J Am Med Assoc 1989:262:2551-2556.
11. Feskens EJM.Havekes LM. KalmijnS.Knijff P.Launer LJ, Kromhout D. Apolipoprotein ε4 allele and cognitive decline in elderly men. Brit Med J 1994; 309:1202-1206.
12. Förstl H, Czech C, Sattel H et al. Apolipoprotein E und Alzheimer-Demenz. Nervenarzt 1994;65:780-786.
13. Goate A, Chartier-Halin MC, Mullan M et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1992,349:704-706.
14. Guo C, Marynen P, Cassiman JJ. A rapid, semiautomated method for apolipoprotein E genotyping. PCR Meth Applicat 1993;2:348-350.
15. Hardy J A, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. TiPS 1991:12:383-388.
16. Hendrie HC, Hall KS, Hui S et al. Apolipoprotein E genotypes and Azlheimer's disease in a community study of elderly African Americans. Ann Neurol 1995:37:118-120.
17. Jones CT, Morris S, Yates CM et al. Mutation in codon 713 of the β-amyloid precursor protein gene presenting with schizophrenia. Nature Genet 1992:1:306-309.
18. Kawamata J, Tanaka S, Shimohama S, Ueda K, Kimura J. Apolipoprotein E polymorphism in Japanese patientes with Alzheimer's disease or vascular dementia J Neurol Neurosurg Psychiatry 1994;57:1414-1416.
19. Kuusisto J, Koivisto K, Kervinen K et al. Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study. Br Med J 1994;309:636-638.
20. Levy-Lahad E, Wasco W, Poorkaj P et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 1995;269:973-977.
21. Levy-Lahad E, Wijsman EM, Nemens E et al. A familial Alzheimer's disease locus on chromosome 1. Science 1995;269: 970-973.
22. Li J, Ma J, Potter H. Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3. Proc Nat Acad Sci USA 1995;92:12180-12184.
23. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622-630.
24. McKhann G, Drachman D, Folstein M, Katzman R Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS/ADRDA workgroup under the auspices of the department of Health and Human services task force on Azheimer's disease. Neurology 1984;34:939-944.
25. McLoughlin DM, Lovestone S. Alzheimer's disease: recent advances in molecular pathology and genetics. Int J Geriatr Psychiatry 1994;9:431-444.
26. Mullan M, Houlden H, Windelspecht M et al. A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α1-antichymotrypsin gene. Nature Genet 1992; 2:340-342.
27. Muramatsu T, Higuchi S, Arai H et al. Apolipoprotein E ε4 allele distribution in alcoholic dementia and in Alzheimer's disease in Japan. Ann Neurol 1994; 36:797-799.
28. Muriel J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 1991;254:97-99.
29. Orrell M, Sahakian B. Education and dementia: research evidence supports the concept "use or loose it". Br Med J 1995;310: 951-952.
30. Ott A, Breteler MMB, van Harskamp F et aL Prevalence of Alzheimer's disease and vascular dementia: association with educationthe Rotterdam study. Br Med J 1995;310:970-973.
31. Payami H, Montee KR, Kaye JA et al Alzheimer's disease, apolipoprotein E4, and gender. J Am Med Assoc 1994;271: 1316-1317.
32. Pericak-Vance MA, Bebout JL, Gaskell PC Jr. et al Linkage studies in familial Alzheimer's disease: evidence for chromosome 19 linkage. Am J Hum Genet 1991 ;48:1034-1050.
33. Poirier J. Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. TiNS 1994;17:525-530.
34. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 1993:342:697-699.
35. Rebeck GW, Perls TT, West HL, Sodhi P, Lipsitz LA, Hyman BT. Reduced apolipoprotein ε4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals. Neurology 1994,44:1513-1516.
36. ReedT, Carmelli D, Swan GE et al. Lower cognitive performance in normal older adult male twins carrying the apolipoprotein Eε4 allele. Arch Neurol 1994.51:1189-1192.
39. Roses AD, Strittmatter WJ, Pericak-Vance M, Corder EH, Saunders AM, Schmechel DE. Clinical application of apolipoprotein E genotyping to Alzheimer's disease. Lancet 1994;343:1564-1565.
40. Saunders AM, Strittmatter WJ, Schmechel D et al. Association of apolipoprotein E allele e4 with late onset familial and sporadic Alzheimer's disease. Neurology 1993;43:1467-1472.
41. Schachter F, Faure-Delanef L, Guenot F et al. Genetic associations with human longevity at the ApoE and ACE loci. Nature Genet 1994,6:29-33.
42. Schmechel DE, Saunders AM, Strittmatter WJ et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Nat Acad Sci USA 1993;90:9649-9653.
43. Selkoe DJ. Alzheimer's disease: a central role for amyloid. J Neuropathol Exp Neurol 1994;53:438-447.
44. Sherrington R, Rogaev EI, Liang Y et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995;375:754-760.
45. Small GW, Mazziotta JC, Collins MT et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. J Am Med Assoc 1995;273:942-947.
46. St. George-Hyslop P, McLachlan DC, Tuda T, Rogaev E. Alzheimer's disease and possible gene interaction. Science 1994:263: 537.
47. Stern Y, Alexander GE, Prohovnik I, Mayeux R. Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer's disease. Ann Neurol 1992,32:371-375.
48. Strittmatter WJ. In: Meeting Briefs - Neuroscientists reach a critical mass in Washington. Science 1993;262:1210-1211.
49. Strittmatter WJ, Saunders AM, Schmechel D et al. Apoplipoprotein E: high avidity binding to the β-amyloid and increased frequency of type 4 allele in late onset familial Alzheimer's disease. Proc Nat Acad Sci USA 1993;90:1977-1981.
50. Strittmatter WJ, Weisgraber H, Huang DY et al. Binding of human apoplipoprotein E to synthetic amyloid β peptide: isoform-specific effects and implications for late onset Alzheimer disease. Proc Nat Acad Sci USA 1993,90:8098-8102.
51. Thompson P, Blessed G. Correlation between the 37 item Mental Test Score and abbreviated 10-item Mental Test Score by psychogeriatric day patients. Br J Psychiatry 1987;151:206-209.
52. Tsai MS, Tangalos EG, Petersen RC et al. Apolipoprotein E: risk factor for Alzheime disease. Am J Hum Genet 1994;54: 643-649.
53. Utermann G. The apolipoprotein E connection. Curr Biol 1994;4:362-365.
54. Van Duijn CM, Stijnen T, Hofman A. Risk factors for Alzheimer's disease: overview of the EURODEM collaborative re-analysis of case-control studies. Int J Epidemiol 1991 ;20: S4-S12.
55. Wenham PR, Price WH, Blundell G. Apolipoprotein E genotyping by one-stage PCR. Lancet 1991 ;337:1158-1159.
56. Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 1992;135:235-238.
57. Zubenko GS, Stiffler S, Stabler S et al. Association of the apolipoprotein E ε4 allele with clinical subtypes of autopsy-confirmed Alzheimer's disease. Am J Med Genet 1994:54:199-205.

Publication Dates

Publication in this collection
10 Nov 2010
Date of issue
1997

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