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. 1991 Jun;48(6):1026–1033.

Segregation analysis reveals evidence of a major gene for Alzheimer disease.

L A Farrer 1, R H Myers 1, L Connor 1, L A Cupples 1, J H Growdon 1
PMCID: PMC1683119  PMID: 2035523

Abstract

In an attempt to resolve the relative influences of major genes, multifactorial heritability, and cohort effects on the susceptibility to Alzheimer disease (AD), complex segregation analysis was performed on 232 nuclear families. All families were consecutively ascertained through a single proband who was referred for diagnostic evaluation of a memory disorder. The results suggest that susceptibility to AD is determined, in part, by a major autosomal dominant allele with an additional multifactorial component. Single-locus, polygenic, sporadic, and no-transmission models, as well as recessive inheritance of the major effect, were significantly rejected. Excess transmission from the heterozygote was marginally significant and probably reflects the presence of phenocopies or perhaps the existence of two or more major loci for AD. The frequency of the AD susceptibility allele was estimated to be .038, but the major locus accounts for only 24% of the transmission variance, indicating a substantial role for other genetic and nongenetic mechanisms in the causation of AD.

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Selected References

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  1. Amaducci L. A., Fratiglioni L., Rocca W. A., Fieschi C., Livrea P., Pedone D., Bracco L., Lippi A., Gandolfo C., Bino G. Risk factors for clinically diagnosed Alzheimer's disease: a case-control study of an Italian population. Neurology. 1986 Jul;36(7):922–931. doi: 10.1212/wnl.36.7.922. [DOI] [PubMed] [Google Scholar]
  2. Bird T. D., Schellenberg G. D., Wijsman E. M., Martin G. M. Evidence for etiologic heterogeneity in Alzheimer's disease. Neurobiol Aging. 1989 Sep-Oct;10(5):432–448. doi: 10.1016/0197-4580(89)90085-7. [DOI] [PubMed] [Google Scholar]
  3. Breitner J. C., Folstein M. F. Familial Alzheimer Dementia: a prevalent disorder with specific clinical features. Psychol Med. 1984 Feb;14(1):63–80. doi: 10.1017/s0033291700003081. [DOI] [PubMed] [Google Scholar]
  4. Breitner J. C., Silverman J. M., Mohs R. C., Davis K. L. Familial aggregation in Alzheimer's disease: comparison of risk among relatives of early-and late-onset cases, and among male and female relatives in successive generations. Neurology. 1988 Feb;38(2):207–212. doi: 10.1212/wnl.38.2.207. [DOI] [PubMed] [Google Scholar]
  5. Chui H. C., Teng E. L., Henderson V. W., Moy A. C. Clinical subtypes of dementia of the Alzheimer type. Neurology. 1985 Nov;35(11):1544–1550. doi: 10.1212/wnl.35.11.1544. [DOI] [PubMed] [Google Scholar]
  6. Farrer L. A., Myers R. H., Cupples L. A., St George-Hyslop P. H., Bird T. D., Rossor M. N., Mullan M. J., Polinsky R., Nee L., Heston L. Transmission and age-at-onset patterns in familial Alzheimer's disease: evidence for heterogeneity. Neurology. 1990 Mar;40(3 Pt 1):395–403. doi: 10.1212/wnl.40.3_part_1.395. [DOI] [PubMed] [Google Scholar]
  7. Farrer L. A., O'Sullivan D. M., Cupples L. A., Growdon J. H., Myers R. H. Assessment of genetic risk for Alzheimer's disease among first-degree relatives. Ann Neurol. 1989 May;25(5):485–493. doi: 10.1002/ana.410250511. [DOI] [PubMed] [Google Scholar]
  8. Folstein M. F. Heterogeneity in Alzheimer's disease. Neurobiol Aging. 1989 Sep-Oct;10(5):434–448. doi: 10.1016/0197-4580(89)90086-9. [DOI] [PubMed] [Google Scholar]
  9. Friedland R. P., Koss E., Haxby J. V., Grady C. L., Luxenberg J., Schapiro M. B., Kaye J. NIH conference. Alzheimer disease: clinical and biological heterogeneity. Ann Intern Med. 1988 Aug 15;109(4):298–311. doi: 10.7326/0003-4819-109-4-298. [DOI] [PubMed] [Google Scholar]
  10. Goate A. M., Haynes A. R., Owen M. J., Farrall M., James L. A., Lai L. Y., Mullan M. J., Roques P., Rossor M. N., Williamson R. Predisposing locus for Alzheimer's disease on chromosome 21. Lancet. 1989 Feb 18;1(8634):352–355. doi: 10.1016/s0140-6736(89)91725-x. [DOI] [PubMed] [Google Scholar]
  11. Heston L. L., Mastri A. R., Anderson V. E., White J. Dementia of the Alzheimer type. Clinical genetics, natural history, and associated conditions. Arch Gen Psychiatry. 1981 Oct;38(10):1085–1090. doi: 10.1001/archpsyc.1981.01780350019001. [DOI] [PubMed] [Google Scholar]
  12. Heston L. L., Mastri A. R. The genetics of Alzheimer's disease: associations with hematologic malignancy and Down's syndrome. Arch Gen Psychiatry. 1977 Aug;34(8):976–981. doi: 10.1001/archpsyc.1977.01770200114017. [DOI] [PubMed] [Google Scholar]
  13. Heyman A., Wilkinson W. E., Hurwitz B. J., Schmechel D., Sigmon A. H., Weinberg T., Helms M. J., Swift M. Alzheimer's disease: genetic aspects and associated clinical disorders. Ann Neurol. 1983 Nov;14(5):507–515. doi: 10.1002/ana.410140503. [DOI] [PubMed] [Google Scholar]
  14. Huff F. J., Auerbach J., Chakravarti A., Boller F. Risk of dementia in relatives of patients with Alzheimer's disease. Neurology. 1988 May;38(5):786–790. doi: 10.1212/wnl.38.5.786. [DOI] [PubMed] [Google Scholar]
  15. Jarvik L. F., Ruth V., Matsuyama S. S. Organic brain syndrome and aging. A six-year follow-up of surviving twins. Arch Gen Psychiatry. 1980 Mar;37(3):280–286. doi: 10.1001/archpsyc.1980.01780160050005. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Katzman R. Alzheimer's disease. N Engl J Med. 1986 Apr 10;314(15):964–973. doi: 10.1056/NEJM198604103141506. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Lalouel J. M., Morton N. E. Complex segregation analysis with pointers. Hum Hered. 1981;31(5):312–321. doi: 10.1159/000153231. [DOI] [PubMed] [Google Scholar]
  20. MORTON N. E. Genetic tests under incomplete ascertainment. Am J Hum Genet. 1959 Mar;11(1):1–16. [PMC free article] [PubMed] [Google Scholar]
  21. Martin J. J., Gheuens J., Bruyland M., Cras P., Vandenberghe A., Masters C. L., Beyreuther K., Dom R., Ceuterick C., Lübke U. Early-onset Alzheimer's disease in 2 large Belgian families. Neurology. 1991 Jan;41(1):62–68. doi: 10.1212/wnl.41.1.62. [DOI] [PubMed] [Google Scholar]
  22. Martin R. L., Gerteis G., Gabrielli W. F., Jr A family-genetic study of dementia of Alzheimer type. Arch Gen Psychiatry. 1988 Oct;45(10):894–900. doi: 10.1001/archpsyc.1988.01800340016002. [DOI] [PubMed] [Google Scholar]
  23. Mayeux R., Stern Y., Spanton S. Heterogeneity in dementia of the Alzheimer type: evidence of subgroups. Neurology. 1985 Apr;35(4):453–461. doi: 10.1212/wnl.35.4.453. [DOI] [PubMed] [Google Scholar]
  24. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E. M. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939–944. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
  25. Morton N. E., MacLean C. J. Analysis of family resemblance. 3. Complex segregation of quantitative traits. Am J Hum Genet. 1974 Jul;26(4):489–503. [PMC free article] [PubMed] [Google Scholar]
  26. Nee L. E., Eldridge R., Sunderland T., Thomas C. B., Katz D., Thompson K. E., Weingartner H., Weiss H., Julian C., Cohen R. Dementia of the Alzheimer type: clinical and family study of 22 twin pairs. Neurology. 1987 Mar;37(3):359–363. doi: 10.1212/wnl.37.3.359. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. SJOGREN T., SJOGREN H., LINDGREN A. G. Morbus Alzheimer and morbus Pick; a genetic, clinical and patho-anatomical study. Acta Psychiatr Neurol Scand Suppl. 1952;82:1–152. [PubMed] [Google Scholar]
  29. Schellenberg G. D., Bird T. D., Wijsman E. M., Moore D. K., Boehnke M., Bryant E. M., Lampe T. H., Nochlin D., Sumi S. M., Deeb S. S. Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease. Science. 1988 Sep 16;241(4872):1507–1510. doi: 10.1126/science.3420406. [DOI] [PubMed] [Google Scholar]
  30. Schoenberg B. S., Anderson D. W., Haerer A. F. Severe dementia. Prevalence and clinical features in a biracial US population. Arch Neurol. 1985 Aug;42(8):740–743. doi: 10.1001/archneur.1985.04210090004002. [DOI] [PubMed] [Google Scholar]
  31. Schoenberg B. S., Kokmen E., Okazaki H. Alzheimer's disease and other dementing illnesses in a defined United States population: incidence rates and clinical features. Ann Neurol. 1987 Dec;22(6):724–729. doi: 10.1002/ana.410220608. [DOI] [PubMed] [Google Scholar]
  32. Silverman J. M., Breitner J. C., Mohs R. C., Davis K. L. Reliability of the family history method in genetic studies of Alzheimer's disease and related dementias. Am J Psychiatry. 1986 Oct;143(10):1279–1282. doi: 10.1176/ajp.143.10.1279. [DOI] [PubMed] [Google Scholar]
  33. St George-Hyslop P. H., Haines J. L., Farrer L. A., Polinsky R., Van Broeckhoven C., Goate A., McLachlan D. R., Orr H., Bruni A. C., Sorbi S. Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder. Nature. 1990 Sep 13;347(6289):194–197. doi: 10.1038/347194a0. [DOI] [PubMed] [Google Scholar]
  34. St George-Hyslop P. H., Myers R. H., Haines J. L., Farrer L. A., Tanzi R. E., Abe K., James M. F., Conneally P. M., Polinsky R. J., Gusella J. F. Familial Alzheimer's disease: progress and problems. Neurobiol Aging. 1989 Sep-Oct;10(5):417–425. doi: 10.1016/0197-4580(89)90082-1. [DOI] [PubMed] [Google Scholar]
  35. St George-Hyslop P. H., Tanzi R. E., Polinsky R. J., Haines J. L., Nee L., Watkins P. C., Myers R. H., Feldman R. G., Pollen D., Drachman D. The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science. 1987 Feb 20;235(4791):885–890. doi: 10.1126/science.2880399. [DOI] [PubMed] [Google Scholar]
  36. Sulkava R., Wikström J., Aromaa A., Raitasalo R., Lehtinen V., Lahtela K., Palo J. Prevalence of severe dementia in Finland. Neurology. 1985 Jul;35(7):1025–1029. doi: 10.1212/wnl.35.7.1025. [DOI] [PubMed] [Google Scholar]
  37. Whalley L. J., Carothers A. D., Collyer S., De Mey R., Frackiewicz A. A study of familial factors in Alzheimer's disease. Br J Psychiatry. 1982 Mar;140:249–256. doi: 10.1192/bjp.140.3.249. [DOI] [PubMed] [Google Scholar]
  38. Zubenko G. S., Huff F. J., Beyer J., Auerbach J., Teply I. Familial risk of dementia associated with a biologic subtype of Alzheimer's disease. Arch Gen Psychiatry. 1988 Oct;45(10):889–893. doi: 10.1001/archpsyc.1988.01800340011001. [DOI] [PubMed] [Google Scholar]

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