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Journal of Molecular Neuroscience

, Volume 17, Issue 2, pp 127–136 | Cite as

Dancing in the dark?

The status of late-onset Alzheimer’s disease genetics
  • Lars Bertram
  • Rudolph E. Tanzi
Article

Abstract

Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder. Recent estimates suggest that possibly over 70% of the genetic variance for the disease remains unaccounted for by apolipoprotein E (APOE) and the three known early-onset AD genes (APP, PSEN1, PSEN2). Specifically, one recent segregation analysis predicted the existence of up to four additional susceptibility genes having a similar or greater effect than APOE. However, most of the nearly three dozen putative AD loci proposed to date have only been inconsistently replicated in follow up analyses and more studies are necessary to distinguish false-positive findings from genuine signals. Novel AD genes will not only provide valuable clues for the development of novel therapeutic approaches, but will also allow the development of new genetic risk-rofiling strategies that are an essential prerequisite for early prediction/prevention of this devastating disease. In this review, we will present a brief overview of analytic tools in complex disease genetics, as well as a summary of recent linkage and association findings indicating the existence of novel late-onset AD genes on chromosomes 12, 10, and 9.

Index Entries

Genetics presenilin genome amyloid Alzheimer’s 

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References

  1. Alvarez V., Alvarez R., Lahoz C. H., et al. (1999) Association between an alpha(2) macroglobulin DNA polymorphism and late-onset Alzheimer’s disease. Biochem. Biophys. Res. Commun. 264, 48–50.PubMedCrossRefGoogle Scholar
  2. Arinami T., Takekoshi K., Yanagi H., et al. (1996) The 5-repeat allele in the very-low-density lipoprotein receptor gene polymorphism is not increased in sporadic Alzheimer’s disease in Japanese. Neurology 47, 1349–1350.PubMedGoogle Scholar
  3. Baum L., Dong Z. Y., Choy K. W., et al. (1998) Low density lipoprotein receptor related protein gene amplification and 766T polymorphism in astrocytomas. Neurosci. Lett. 256, 5–8.PubMedCrossRefGoogle Scholar
  4. Bertram L., Blacker D., Crystal A., et al. (2001) Candidate genes showing no evidence of association with AD: results of the NIMH-AD Genetics Initiative, in Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics (Iqbad. K., Sisodia S., and Winblad B., eds.), Chichester, U K, J. Wiley & Sons, Ltd., pp. 45–53.Google Scholar
  5. Bertram L., Blacker D., Crystal A., et al. (2000a). Candidate genes showing no evidence for association or linkage with Alzheimer’s disease using family-based methodologies. Exp. Gerontol. 35, 1353–1361.PubMedCrossRefGoogle Scholar
  6. Bertram L., Blacker D., Mullin K., et al. (2000b) Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science 290, 2302–2303.PubMedCrossRefGoogle Scholar
  7. Bertram L. and Tanzi R. E. (2001) Of replications and refutations: the status of Alzheimer’s disease genetics research. Curr. Neurol. Neurosci. Rep. 1, 442–450.PubMedCrossRefGoogle Scholar
  8. Blacker D., Haines J. L., Rodes L., et al. (1997) ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology 48, 139–147.PubMedGoogle Scholar
  9. Blacker D., Wilcox M. A., Laird N. M., et al. (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer’s disease. Nat. Genet. 19, 357–360.PubMedCrossRefGoogle Scholar
  10. Bullido M. J., Artiga M. J., Recuero M., et al. (1998) A polymorphism in the regulatory region of APOE associated with risk for Alzheimer’s dementia. Nat. Genet. 18, 69–71.PubMedCrossRefGoogle Scholar
  11. Corder E. H., Saunders A. M., Risch N. J., et al. (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7, 180–184.PubMedCrossRefGoogle Scholar
  12. Daw E. W., Payami H., Nemens E. J., et al. (2000) The number of trait loci in late-onset Alzheimer disease. Am. J. Hum. Genet. 66, 196–204.PubMedCrossRefGoogle Scholar
  13. Dodel R. C., Du Y., Bales K. R., et al. (2000) Alpha2 macroglobulin and the risk of Alzheimer’s disease. Neurology 54, 438–442.PubMedGoogle Scholar
  14. Durner M., Vieland V. J., and Greenberg D. A. (1999) Further evidence for the increased power of LOD scores compared with nonparametric methods. Am. J. Hum. Genet. 64, 281–289.PubMedCrossRefGoogle Scholar
  15. Ertekin-Taner N., Graff-Radford N., Younkin L. H., et al. (2000) Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science 290, 2303–2304.PubMedCrossRefGoogle Scholar
  16. Fallin D., Cohen A., Essioux L., et al. (2001) Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer’s disease. Genome Res. 11, 143–151.PubMedCrossRefGoogle Scholar
  17. Fallin D., Gauntlett A. C., Scibelli P., et al. (1997) No association between the very low density lipoprotein receptor gene and late-onset Alzheimer’s disease nor interaction with the apolipoprotein E gene in population-based and clinic samples. Genet. Epidemiol. 14, 299–305.PubMedCrossRefGoogle Scholar
  18. Farrer L. A., Cupples L. A., Haines J. L., et al. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278, 1349–1356.PubMedCrossRefGoogle Scholar
  19. Feuk L., Prince J. A., Breen G., et al. (2000) apolipoprotein-E dependent role for the FAS receptor in early onset Alzheimer’s disease: finding of a positive association for a polymorphism in the TNFRSF6 gene. Hum. Genet. 107, 391–396.PubMedCrossRefGoogle Scholar
  20. Goate A., Chartier-Harlin M. C., Mullan M., et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706.PubMedCrossRefGoogle Scholar
  21. Greenberg D. A., Abreu P., and Hodge S. E. (1998). The power to detect linkage in complex disease by means of simple LOD-score analyses. Am. J. Hum. Genet. 63, 870–879.PubMedCrossRefGoogle Scholar
  22. NIMH Genetics Initiative AD Study Group (submitted). Results of a high resolution genome screen of 437 Alzheimer’s disease families: The NIMH Genetics Initiative.Google Scholar
  23. Helbecque N., Berr C., Cottel D., et al. (2001) VLDL receptor polymorphism, cognitive impairment, and dementia. Neurology 56, 1183–1188.PubMedGoogle Scholar
  24. Helbecque N., Richard F., Cottel D., et al. (1998) The very low density lipoprotein (VLDL) receptor is a genetic susceptibility factor for Alzheimer disease in a European Caucasian population. Alzheimer Dis. Assoc. Disord. 12, 368–371.PubMedCrossRefGoogle Scholar
  25. Jhoo J. H., Kim K. W., Lee D. Y., et al. (2001) Association of alpha-2-macroglobulin deletion polymorphism with sporadic Alzheimer’s disease in Koreans. J. Neurol. Sci. 184, 21–25.PubMedCrossRefGoogle Scholar
  26. Kamboh M. I., Ferrell R. E., and DeKosky S. T. (1998) Genetic association studies between Alzheimer’s disease and two polymorphisms in the low density lipoprotein receptor-related protein gene. Neurosci. Lett. 244, 65–68.PubMedCrossRefGoogle Scholar
  27. Kang D. E., Saitoh T., Chen X., et al. (1997) Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer’s disease. Neurology 49, 56–61.PubMedGoogle Scholar
  28. Kehoe P., Wavrant-De Vrieze F., Crook R., et al. (1999) A full genome scan for late onset Alzheimer’s disease. Hum. Mol. Genet. 8, 237–245.PubMedCrossRefGoogle Scholar
  29. Koster M. N., Dermaut B., Cruts M., et al. (2000) The alpha2-macroglobulin gene in AD: a population-based study and meta-analysis. Neurology 55, 678–684.PubMedGoogle Scholar
  30. Lambert J. C., Berr C., Pasquier F., et al. (1998a). Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer’s disease. Hum. Mol. Genet. 7, 1511–1516.PubMedCrossRefGoogle Scholar
  31. Lambert J. C., Goumidi L., Vrieze F. W., et al. (2000) The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer’s disease. Hum. Mol. Genet. 9, 2275–2280.PubMedCrossRefGoogle Scholar
  32. Lambert J. C., Wavrant-De Vrieze F., Amouyel P., et al. (1998b) Association at LRP gene locus with sporadic late-onset Alzheimer’s disease. Lancet 351, 1787–1788.PubMedCrossRefGoogle Scholar
  33. Lander E. and Kruglyak L. (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247.PubMedCrossRefGoogle Scholar
  34. Levy-Lahad E., Wasco W., Poorkaj P., et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.PubMedCrossRefGoogle Scholar
  35. Liao A., Nitsch R. M., Greenberg S. M., et al. (1998) Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer’s disease. Hum. Mol. Genet. 7, 1953–1956.PubMedCrossRefGoogle Scholar
  36. Majores M., Bagli M., Papassotiropoulos A., et al. (2000) Allelic association between the D10S1423 marker and Alzheimer’s disease in a German population. Neurosci. Lett. 289, 224–226.PubMedCrossRefGoogle Scholar
  37. Martin E. R., Lai E. H., Gilbert J. R., et al. (2000) SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease. Am. J. Hum. Genet. 67, 383–394.PubMedCrossRefGoogle Scholar
  38. McIlroy S. P., Vahidassr M. D., Savage D. A., et al. (1999) Risk of Alzheimer’s disease is associated with a very low-density lipoprotein receptor genotype in Northern Ireland. Am. J. Med. Genet. 88, 140–144.PubMedCrossRefGoogle Scholar
  39. Meyer M. R., Tschanz J. T., Norton M. C., et al. (1998) APOE genotype predicts when—not whether—one is predisposed to develop Alzheimer disease. Nat. Genet. 19, 321–322.PubMedCrossRefGoogle Scholar
  40. Myers A., Holmans P., Marshall H., et al. (2000) Susceptibility locus for Alzheimer’s disease on chromosome 10. Science 290, 2304–2305.PubMedCrossRefGoogle Scholar
  41. Myllykangas L., Polvikoski T., Sulkava R., et al. (1999) Genetic association of alpha2-macroglobulin with Alzheimer’s disease in a Finnish elderly population. Ann. Neurol. 46, 382–390.PubMedCrossRefGoogle Scholar
  42. Nacmias B., Latorraca S., Piersanti P., et al. (1995). ApoE genotype and familial Alzheimer’s disease: a possible influence on age of onset in APP717 Val→lle mutated families. Neurosci. Lett. 183, 1–3.PubMedCrossRefGoogle Scholar
  43. Nacmias B., Tedde A., Cellini E., et al. (2001) alpha2-Macroglobulin polymorphisms in Italian sporadic and familial Alzheimer’s disease. Neurosci. Lett. 299, 9–12.PubMedCrossRefGoogle Scholar
  44. Okuizumi K., Onodera O., Namba Y., et al. (1995) Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer’s disease. Nat. Genet. 11, 207–209.PubMedCrossRefGoogle Scholar
  45. Ott J. (1999) Analysis of Human Genetic Linkage. Johns Hopkins University Press, Baltimore, MD.Google Scholar
  46. Pericak-Vance M. A., Bass M. P., Yamaoka L. H., et al. (1997) Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 278, 1237–1241.PubMedCrossRefGoogle Scholar
  47. Pericak-Vance M. A., Bebout J. L., Gaskell P. C., et al. (1991) Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am. J. Hum. Genet. 48, 1034–1050.PubMedGoogle Scholar
  48. Pericak-Vance M. A., Grubber J., Bailey L. R., et al. (2000) Identification of novel genes in late-onset Alzheimer’s disease. Exp. Gerontol. 35, 1343–1352.PubMedCrossRefGoogle Scholar
  49. Poirier J. (2000) Apolipoprotein E and Alzheimer’s disease. A role in amyloid catabolism. Ann. NY Acad. Sci. 924, 81–90.PubMedCrossRefGoogle Scholar
  50. Pritchard M. L., Saunders A. M., Gaskell P. C., et al. (1996) No association between very low density lipoprotein receptor (VLDL-R) and Alzheimer disease in American Caucasians. Neurosci. Lett. 209, 105–108.PubMedCrossRefGoogle Scholar
  51. Risch N. and Merikangas K. (1996) The future of genetic studies of complex human diseases. Science 273, 1516–1517.PubMedCrossRefGoogle Scholar
  52. Risch N. J. (2000) Searching for genetic determinants in the new millennium. Nature 405, 847–856.PubMedCrossRefGoogle Scholar
  53. Rogaev E. I., Sherrington R., Rogaeva E. A., et al. (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778.PubMedCrossRefGoogle Scholar
  54. Rogaeva E., Premkumar S., Song Y., et al. (1998) Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. JAMA 280, 614–618.PubMedCrossRefGoogle Scholar
  55. Romas S. N., Mayeux R., Rabinowitz D., et al. (2000) The deletion polymorphism and Val1000lle in alpha-2-macroglobulin and Alzheimer disease in Caribbean Hispanics. Neurosci. Lett. 279, 133–136.PubMedCrossRefGoogle Scholar
  56. Roses A. D., Devlin B., Coneally P. M., et al. (1995) Measuring the genetic contribution of APOE in late-onset Alzheimer disease. Am. J. Hum. Genet. Suppl. 57, A202.Google Scholar
  57. Satten G. A., Flanders W. D., and Yang Q. (2001) Accounting for unmeasured population substructure in case-control studies of genetic association using a novel latent-class model. Am. J. Hum. Genet. 68, 466–477.PubMedCrossRefGoogle Scholar
  58. Saunders A. M., Strittmatter W. J., Schmechel D., et al. (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43, 1467–1472.PubMedGoogle Scholar
  59. Schmechel D. E., Saunders A. M., Strittmatter W. J., et al. (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 9649–9653.PubMedCrossRefGoogle Scholar
  60. Scott W. K., Grubber J., Coneally P. M., et al. (2000) Fine-mapping of the chromosome 12 Alzheimer disease locus using family-based association tests of microsatellite markers. Neurobiol. Aging 21, S129.Google Scholar
  61. Scott W. K., Yamaoka L. H., Bass M. P., et al. (1998) No genetic association between the LRP receptor and sporadic or late-onset familial Alzheimer disease. Neurogenetics 1, 179–183.PubMedCrossRefGoogle Scholar
  62. Sherrington R., Rogaev E. I., Liang Y., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760.PubMedCrossRefGoogle Scholar
  63. Spielman R. S., McGinnis R. E., and Ewens W. J. (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516.PubMedGoogle Scholar
  64. Strittmatter W. J., Saunders A. M., Schmechel D., et al. (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981.PubMedCrossRefGoogle Scholar
  65. Tanzi R. E. (1999) A genetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders. J. Clin. Invest. 104, 1175–1179.PubMedCrossRefGoogle Scholar
  66. Tanzi R. E., Gusella J. F., Watkins P. C., et al. (1987) Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235, 880–884.PubMedCrossRefGoogle Scholar
  67. Taylor A. E., Yip A., Brayne C., et al. (2001) Genetic association of an LBP-1c/CP2/LSF gene polymorphism with late onset Alzheimer’s disease. J. Med. Genet. 38, 232–233.PubMedCrossRefGoogle Scholar
  68. Vekrellis K., Ye Z., Qiu W. Q., et al. (2000) Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J. Neurosci. 20, 1657–1665.PubMedGoogle Scholar
  69. Verpillat P., Bouley S., Hannequin D., et al. (2000) Alpha2-macroglobulin gene and Alzheimer’s disease: confirmation of association by haplotypes analyses. Ann. Neurol. 48, 400–402.PubMedCrossRefGoogle Scholar
  70. Woodward R., Singleton A. B., Gibson A. M., et al. (1998) LRP gene and late-onset Alzheimer’s disease. Lancet 352, 239–240.PubMedCrossRefGoogle Scholar
  71. Wu W. S., Holmans P., Wavrant-DeVrieze F., et al. (1998) Genetic studies on chromosome 12 in late-onset Alzheimer disease. JAMA 280, 619–622.PubMedCrossRefGoogle Scholar
  72. Zubenko G. S., Hughes H. B., Stiffler J. S., et al. (1998) A genome survey for novel Alzheimer disease risk loci: results at 10-cM resolution. Genomics 50, 121–128.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  1. 1.Genetics and Aging Research Unit, Department of Neurology and Center for Aging, Genetics and NeurodegenerationMassachusetts General Hospital Harvard Medical SchoolCharlestown

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