Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1991 Mar;48(3):563–583.

Linkage analysis of familial Alzheimer disease, using chromosome 21 markers

Gerard D Schellenberg, Margaret A Pericak-Vance, Ellen M Wijsman, Deborah K Moore, Perry C Gaskell, Larry A Yamaoka, Jacqueline L Bebout, Leojean Anderson, Kathleen A Welsh, Christopher M Clark, George M Martin, Allen D Roses, Thomas D Bird
PMCID: PMC1682988  PMID: 1998342

Abstract

Chromosome 21 markers were tested for linkage to familial Alzheimer disease (FAD) in 48 kindreds. These families had multiple cases of Alzheimer disease (AD) in 2 or more generations with family age-at-onset means (M) ranging from 41 to 83 years. Included in this group are seven Volga German families which are thought to be genetically homogeneous with respect to FAD. Autopsy documentation of AD was available for 32 families. Linkage to the 21 q11-q21 region was tested using D21S16, D21S13, D21S110, D21S1/S11, and the APP gene as genetic markers. When linkage results for all the families were summed, the LOD scores for these markers were consistently negative and the entire region was formally excluded. Linkage results were also summed for the following family groups; late-onset (M > 60), early-onset (M ≤ 60), Volga Germans (M = 56), and early-onset non–Volga Germans (M ≤ 60). For the first three groups, LOD scores were negative for this region. For the early-onset non–Volga German group (six families), small positive LOD scores of Zmax = 0.78 (recombination fraction θ = .15), Zmax = 0.27 (θ = .15), and Zmax = 0.64 (θ = .0), were observed for D21S13, D21S16, and D21S110, respectively. The remainder of the long arm of chromosome 21 was tested for linkage to FAD using seven markers spanning the q22 region. Results for these markers were also predominantly negative. Thus it is highly unlikely that a chromosome 21 gene is responsible for late-onset FAD and at least some forms of early-onset FAD represented by the Volga German kindreds.

Full text

PDF
563

Selected References

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

  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., Lampe T. H., Nemens E. J., Miner G. W., Sumi S. M., Schellenberg G. D. Familial Alzheimer's disease in American descendants of the Volga Germans: probable genetic founder effect. Ann Neurol. 1988 Jan;23(1):25–31. doi: 10.1002/ana.410230106. [DOI] [PubMed] [Google Scholar]
  3. Bird T. D., Sumi S. M., Nemens E. J., Nochlin D., Schellenberg G., Lampe T. H., Sadovnick A., Chui H., Miner G. W., Tinklenberg J. Phenotypic heterogeneity in familial Alzheimer's disease: a study of 24 kindreds. Ann Neurol. 1989 Jan;25(1):12–25. doi: 10.1002/ana.410250104. [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. 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]
  6. Goudsmit J., White B. J., Weitkamp L. R., Keats B. J., Morrow C. H., Gajdusek D. C. Familial Alzheimer's disease in two kindreds of the same geographic and ethnic origin. A clinical and genetic study. J Neurol Sci. 1981 Jan;49(1):79–89. doi: 10.1016/0022-510x(81)90190-8. [DOI] [PubMed] [Google Scholar]
  7. Heston L. L. Alzheimer's disease, trisomy 21, and myeloproliferative disorders: associations suggesting a genetic diathesis. Science. 1977 Apr 15;196(4287):322–323. doi: 10.1126/science.196.4287.322. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. 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]
  10. Keats B., Ott J., Conneally M. Report of the committee on linkage and gene order. Cytogenet Cell Genet. 1989;51(1-4):459–502. doi: 10.1159/000132805. [DOI] [PubMed] [Google Scholar]
  11. Kidd K. K., Bowcock A. M., Schmidtke J., Track R. K., Ricciuti F., Hutchings G., Bale A., Pearson P., Willard H. F., Gelernter J. Report of the DNA committee and catalogs of cloned and mapped genes and DNA polymorphisms. Cytogenet Cell Genet. 1989;51(1-4):622–947. doi: 10.1159/000132810. [DOI] [PubMed] [Google Scholar]
  12. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Mohs R. C., Breitner J. C., Silverman J. M., Davis K. L. Alzheimer's disease. Morbid risk among first-degree relatives approximates 50% by 90 years of age. Arch Gen Psychiatry. 1987 May;44(5):405–408. doi: 10.1001/archpsyc.1987.01800170019003. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Nee L. E., Polinsky R. J., Eldridge R., Weingartner H., Smallberg S., Ebert M. A family with histologically confirmed Alzheimer's disease. Arch Neurol. 1983 Apr;40(4):203–208. doi: 10.1001/archneur.1983.04050040033004. [DOI] [PubMed] [Google Scholar]
  17. Oliver C., Holland A. J. Down's syndrome and Alzheimer's disease: a review. Psychol Med. 1986 May;16(2):307–322. doi: 10.1017/s0033291700009120. [DOI] [PubMed] [Google Scholar]
  18. Ott J. Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet. 1974 Sep;26(5):588–597. [PMC free article] [PubMed] [Google Scholar]
  19. Owen M. J., James L. A., Hardy J. A., Williamson R., Goate A. M. Physical mapping around the Alzheimer disease locus on the proximal long arm of chromosome 21. Am J Hum Genet. 1990 Feb;46(2):316–322. [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. 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]
  23. 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]
  24. Tanzi R. E., Haines J. L., Watkins P. C., Stewart G. D., Wallace M. R., Hallewell R., Wong C., Wexler N. S., Conneally P. M., Gusella J. F. Genetic linkage map of human chromosome 21. Genomics. 1988 Aug;3(2):129–136. doi: 10.1016/0888-7543(88)90143-7. [DOI] [PubMed] [Google Scholar]
  25. Tanzi R. E., St George-Hyslop P. H., Haines J. L., Polinsky R. J., Nee L., Foncin J. F., Neve R. L., McClatchey A. I., Conneally P. M., Gusella J. F. The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid beta-protein gene. Nature. 1987 Sep 10;329(6135):156–157. doi: 10.1038/329156a0. [DOI] [PubMed] [Google Scholar]
  26. Van Broeckhoven C., Genthe A. M., Vandenberghe A., Horsthemke B., Backhovens H., Raeymaekers P., Van Hul W., Wehnert A., Gheuens J., Cras P. Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families. Nature. 1987 Sep 10;329(6135):153–155. doi: 10.1038/329153a0. [DOI] [PubMed] [Google Scholar]
  27. Warren A. C., Slaugenhaupt S. A., Lewis J. G., Chakravarti A., Antonarakis S. E. A genetic linkage map of 17 markers on human chromosome 21. Genomics. 1989 May;4(4):579–591. doi: 10.1016/0888-7543(89)90282-6. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES