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Apolipoprotein E4 allele and Alzheimer disease: Examination of Allelic association and effect on age at onset in both early-and late-onset cases
P. A. Locke,
P. M. Conneally,
R. E. Tanzi,
J. F. Gusella,
J. L. Haines,
P. A. Locke
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown
Search for more papers by this authorP. M. Conneally
Department of Medical and Molecular Genetics, Indiana University Medical Center, Indianapolis
Search for more papers by this authorR. E. Tanzi
Laboratory of Genetics and Aging, Massachusetts General Hospital, Charlestown
Search for more papers by this authorJ. F. Gusella
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown
Search for more papers by this authorCorresponding Author
J. L. Haines
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown
Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 6th Floor, Charlestown, MA 02129Search for more papers by this authorP. A. Locke,
P. M. Conneally,
R. E. Tanzi,
J. F. Gusella,
J. L. Haines,
P. A. Locke
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown
Search for more papers by this authorP. M. Conneally
Department of Medical and Molecular Genetics, Indiana University Medical Center, Indianapolis
Search for more papers by this authorR. E. Tanzi
Laboratory of Genetics and Aging, Massachusetts General Hospital, Charlestown
Search for more papers by this authorJ. F. Gusella
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown
Search for more papers by this authorCorresponding Author
J. L. Haines
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown
Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 6th Floor, Charlestown, MA 02129Search for more papers by this authorAbstract
An increased frequency of the apolipoprotein E type 4 allele (APOE-4) has previously been associated with both late-onset sporadic and late-onset familial Alzheimer disease (AD) [Strittmatter et al. (1993) Proc Natl Acad Sci USA 90:1977–1981; Saunders et al. (1993a) Neurology 43:1467–1472]. To further investigate this association we genotyped affected individuals from 92 separate AD pedigrees including both early- and late-onset cases. An increased frequency of the APOE-4 allele was found only among the late-onset cases, both familial and sporadic, confirming the earlier reports. In addition, age at onset was significantly decreased in the APOE-4 homozygotes (in late onset families) compared to either APOE-4 heterozygotes or individuals not carrying an APOE-4 allele. We also observed a significantly decreased frequency of the APOE-2 allele in both the early-and late-onset familial cases. These results strengthen the argument for a direct role of APOE in susceptibility to AD. © Wiley-Liss, Inc.
References
-
Anderson MA, and
Gusella JF
(1984):
Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines.
In Vitro
11:
856–858.
10.1007/BF02619631 Google Scholar
- Boehnke M (1991): Allele frequency estimation from data on relatives. Am J Hum Genet 48: 22–25.
- Corain B, Iqbal K, Nicolini M (1993): “ Alzheimer's Disease: Advances in Clinical and Basic Research.” Chichester: John Wiley, pp 1–2.
- 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.
- Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr., Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1994): Apolipoprotein E type 2 allele decreases the risk of late onset Alzheimer disease. Nat Genet 7: 180–184.
- Farrer LA, Myers RH, Connor L, Cupples A, Growdon JH (1991): Segregation analysis reveals evidence for a major gene in familial Alzheimer's disease. Am J Hum Genet 48: 1026–1033.
- Fumeron F, Rigaud D, Bertiere MC, Bardon S, Dely C, Appelbaum M (1988): Association of apolipoprotein E4 allele with hypertriglyceridemia in obesity. Clin Genet 34: 258–264.
- Goate AM, Chartier-Harlin MC, Mullan MC, Brown J, Crawford F, Fidani L, Guiffra A, Haynes A, et al. (1991): Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349: 704–706.
- Hallman DM, Boerwinkle E, Saha N, Sandholzer C, Menzel HJ, Csazar A, Utermann G (1991): The Apolipoprotein E polymorphism: A comparison of allele frequencies and effects in nine populations. Am J Hum Genet 49: 338–349.
- Hardy J, and the Alzheimer's Disease Collaborative Group (1993): Apolipoprotein E and Alzheimer's Disease. Lancet 342: 737–738.
- Hendricks L, Van Dujjn CM, Cras P, et al. (1992): Presenile dementia and cerebral hemorrhage linked to mutation at codon 692 of the β-amyloid precursor protein gene. Nature Genet 1: 218–221.
- Hixson JE, Vernier DT (1990): Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I. J Lipid Res 31: 545–548.
- Karlinksy H, Vaula G, Haines JL, et al. (1992): Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation in codon 717 of the β-amyloid precursor protein gene. Neurology 42: 1445–1453.
- McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E (1984): Clinical diagnosis of Alzheimer's disease. Report of the NINCD-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34: 939–944.
- Menzel H-J, Kladetzky R-G, Assmann G (1983): Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis 3: 310–315.
- Mullan M, Houlden H, Windelspecht M, Fidani L, Lombardi C, Diaz P, Rossor M, Crook R, Hardy J, Crawford F (1992a): A locus for familial Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha-1-antichymotrypsin gene. Nat Genet 2: 340–342.
- Mullan M, Crawford F, Axelman K, et al. (1992b): A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of the β-amyloid. Nat Genet 1: 345–347.
- Murrell J, Farlow M, Ghetti B, Benson MD (1991): A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254: 97–99.
- Noguchi S, Murakami K, Yamada N (1993): Apolipoprotein E genotype and Alzheimer's disease. Lancet 342: 737.
- Payami H, Kaye J, Heston LL, et al. (1993): Apolipoprotein E genotype and Alzheimer's disease. Lancet 342: 737–738.
- Pericak-Vance MA, Bebout JL, Gaskell PC, Yamaoka LH, Hung WY, Alberts MJ, Walker AP, Barlett RJ, Haynes CA, Welsh KA, Earl NL, Heyman A, Clark CM, and Roses AD (1991): Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet 48: 1034–1050.
- Poirier J, Davignon J, Bouthillier D, et al. (1993): Apolipoprotein E and Alzheimer's disease. Lancet 342: 697–699.
- Saunders AM, Strittmatter WJ, Schmechel DE, St George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BA, Gusella JF, Crapper-MacLachlan DR, Growden J, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD (1993a): Association of apolipoprotein E allele E4 with late onset familial and sporadic Alzheimer's disease. Neurology 43: 1467–1472.
- Saunders AM, Schmader K, Breitner JCS, Benson MD, Brown WT, Goldfarb D, Manwaring MG, Szy-manski MH, McCown N, Dole KC, Schmechel DE, Strittmatter WJ, Pericak-Vance MA, Roses AD (1993b): Apolipoprotein ϵ 4 allele distributions in late-onset Alzheimer's disease and other amyloid-forming disease. Lancet 342: 710–711.
- Schellenberg GD, Deeb SS, Boehnke ML, Bryant EM, Martin GM, Lampe TH, Bird TD (1987): Association of apolipoprotein CII allele with familial dementia of the Alzheimer type. J Neurogenet 4: 97–108.
- Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, Potter H, Heston LL, Martin J (1992): Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258: 668–671.
- Smit M, de Knijff P, Rosseneu M, Bury J, Klasen E, Frants R, Havekes L (1988): Apolipoprotein E polymorphism in the Netherlands and its effect on plasma lipid and apolipoprotein levels. Am J Hum Genet 80: 287–292.
- St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, et al. (1987): The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 235: 885–889.
- St George-Hyslop PH, Haines JL, Farrer LA, Polinsky R, Van Broeckhoven, Goate A, Crapper-McLachlan DR, Orr H, Bruni AC, Sorbi S, Rainero I, Foncin JF, Pollen D, Cantu JM, Tupler R, Voskresenskaya N, Mayeux R, Growdon J, Nee L, Backhovens H, Martin JJ, Rossor M, Owen MJ, Mullan M, Percy ME, Karlinsky H, Rich S, Heston L, Montes M, Mortilla M, Nacmias N, Vaula G, Gusella JF, Hardy JA (1990): Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous entity. Nature 347: 194–197.
- St George-Hyslop PH, Haines JL, Rogaev E, Mortilla M, Vaula G, Pericak-Vance MA, Foncin JF, Montese M, Bruni A, Sorbi S, Rainero I, Pinessi L, Pollen D, Polinsky R, Nee L, Kennedy J, Macciardi F, Rogaeva E, Liang Y, Alexandrova N, Lukiw W, Schlumpf K, Tanzi RE, Tsuda T, Farrer LA, Cantu JM, Duara R, Amaducci L, Bergamini L, Gusella JF, Roses AD, Crapper-McLachlan D (1992): Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat Genet 2: 330–334.
- Strittmatter WJ, Saunders AM, Schmechel DE, Pericak-Vance MA, Enghild J, Salvesen GS, Roses AD (1993): Apolipoprotein E: high-avidity binding to B-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90: 1977–1981.
- Tanzi RE, Vaula G, Romano DM, Mortilla M, Huang TL, Tupler RG, Wasco W, Hyman BT, Haines JL, Jenkins BJ, Kalaitsidaki M, Warren AC, McInnis MC, Antonarakis SE, Karlinsky H, Percy ME, Connor L, Growdon J, Crapper-Mclachlan DR, Gusella JF, St George-Hyslop PH (1992): Assessment of amyloid β protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases. Am J Hum Genet 51: 273–282.
- Tsai M-S, Tangalos EG, Petersen RC, Smith GE, Schaid DJ, Kokmen E, Ivnik RJ, Thibodeau SN (1994): Apolipoprotein E: risk factor for Alzheimer disease. Am J Hum Genet 643–649.
- Van Bockxmeer FM, Mamotte CD (1992): Apolipoprotein epsilon 4 homozygosity in young men with coronary heart disease. Lancet 340: 879–880.
- Van Broeckhoven C, Backhovens H, Cruts M, De Winter G, Bruyland M, Cras P, Martin J-J (1992): Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3. Nat Genet 2: 334–339.
- Weeks DE, Lange K (1988): The affected-pedigree-member method of linkage analysis. Am J Hum Genet 42: 315–326.
- Wenham PR, Price WH, Blundell G (1991): Apolipoprotein E genotyping by one-stage PCR. Lancet 337: 1158–1159.
- Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y (1991): The 717Val > lle substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups. Biochem Biophys Res Commun 178: 1141–1146.
- Yu C-E, Payami H, Olson JM, Boehnke M, Wijsman EM, Orr HT, Kukull WA, Goddard KAB, Nemans E, White JA, Alonso ME, Taylor TD, Ball MJ, Kaye J, Morris J, Chui H, Sadovnick AD, Martin GM, Larson EB, Heston LL, Bird TD, Schellenberg GD (1994): The apolipoprotein E/CI/CII gene cluster and late onset Alzheimer disease. Am J Hum Genet 54: 631–642.
