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Table of Contents
Vol. 1, No. 4-5, 2004
Issue release date: November 2004
Neurodegenerative Dis 2004;1:213–217
(DOI:10.1159/000080988)

Problems and Solutions in the Genetic Analysis of Late-Onset Alzheimer’s Disease

Hardy J. · Myers A. · Wavrant-De Vrieze F.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Md., USA
email Corresponding Author

Abstract

The identification of the apolipoprotein E gene as a risk factor for late-onset Alzheimer’s disease was a spectacularly successful application of genetic analysis to a complex trait, and it led to the hope and expectation that other risk loci for the disease would soon be forthcoming. Twelve years later, despite a huge amount of work, no other loci have been identified. In this article, we discuss the complexity of the problem and the pitfalls in the analytical methods that have been used and how we are approaching this problem.


 goto top of outline Key Words

  • Alzheimer’s disease
  • Apolipoprotein E
  • Amyloid protein precursor
  • Presenilin

 goto top of outline Abstract

The identification of the apolipoprotein E gene as a risk factor for late-onset Alzheimer’s disease was a spectacularly successful application of genetic analysis to a complex trait, and it led to the hope and expectation that other risk loci for the disease would soon be forthcoming. Twelve years later, despite a huge amount of work, no other loci have been identified. In this article, we discuss the complexity of the problem and the pitfalls in the analytical methods that have been used and how we are approaching this problem.

Copyright © 2004 S. Karger AG, Basel


 goto top of outline References
  1. Goate AM, Chartier-Harlin MC, Mullan MC, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor MN, Owen M, Hardy J: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991;349:704–706.
  2. Sherrington R, Rogaev EL, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HAR, Haines JL, Pericak Vance M, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George Hyslop PH: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754–760.
  3. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al: Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995;269:973–977.
  4. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al: 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 1995;376:775–778.
  5. Hardy J: Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 1997;20:154–159.
  6. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;13:921–923.
  7. Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V, et al: Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer’s disease: Analysis of the 19q13.2 chromosomal region. Hum Mol Genet 1994;3:569–574.
  8. Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, et al: Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 1999;96:15233–15238.
  9. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G: Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439–1443.
  10. Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmidt SD, et al: A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 2001;8:890–899.
  11. Lucotte G, Visvikis S, Leininger-Muler B, David F, Berriche S, Reveilleau S, Couderc R, Babron MC, Aguillon D, Siest G: Association of apolipoprotein E allele epsilon 4 with late-onset sporadic Alzheimer’s disease. Am J Med Genet 1994;54:286–288.
  12. Henderson AS, Easteal S, Jorm AF, Mackinnon AJ, Korten AE, Christensen H, Croft L, Jacomb PA: Apolipoprotein E allele epsilon 4, dementia, and cognitive decline in a population sample. Lancet 1995;346:1387–1390.
  13. Ritchie K, Kotzki PO, Touchon J, Cristol JP: Characteristics of Alzheimer’s disease patients with and without ApoE4 allele. Lancet 1996;348:960.
  14. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM: 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. Ann Neurol 1995;38:797–808.
  15. Daw EW, Heath SC, Wijsman EM: Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer disease pedigrees. Am J Hum Genet 1999;64:839–851.
  16. Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE, Perry RT, Bassett SS, Chase G, Meyers D, Albert MS, Tanzi R: ApoE-4 and age at onset of Alzheimer’s disease: The NIMH genetics initiative. Neurology 1997;48:139–147.
  17. Kehoe P, Wavrant-De Vrieze F, Crook R, Wu WS, Holmans P, Fenton I, Spurlock G, Norton N, Williams H, Williams N, Lovestone S, Pérez-Tur J, Hutton M, Chartier-Harlin MC, Shears S, Roehl K, Booth J, Van Voorst W, Ramic D, Williams J, Goate A, Hardy J, Owen MJ: A full genome scan for late onset Alzheimer’s disease. Hum Mol Genet 1999;8:237–245.
  18. Myers A, Wavrant-De Vrieze F, Holmans P, Hamshere M, Crook R, Compton D, Marshall H, Meyer D, Shears S, Booth J, Ramic D, Knowles H, Morris JC, Williams N, Norton N, Abraham R, Kehoe P, Williams H, Rudrasingham V, Rice F, Giles P, Tunstall N, Jones L, Lovestone S, Williams J, Owen MJ, Hardy J, Goate A: Full genome screen for Alzheimer disease: Stage II analysis. Am J Med Genet 2002;114:235–244.
  19. Pericak-Vance MA, Grubber J, Bailey LR, Hedges D, West S, Santoro L, Kemmerer B, Hall JL, Saunders AM, Roses AD, Small GW, Scott WK, Conneally PM, Vance JM, Haines JL: Identification of novel genes in late-onset Alzheimer’s disease. Exp Gerontol 2000;35:1343–1352.
  20. Romas SN, Santana V, Williamson J, Ciappa A, Lee JH, Rondon HZ, Estevez P, Lantigua R, Medrano M, Torres M, Stern Y, Tycko B, Mayeux R: Familial Alzheimer disease among Caribbean Hispanics: A reexamination of its association with APOE. Arch Neurol 2002;59:87–91.
  21. Chataway J, Feakes R, Coraddu F, Gray J, Dea J, Fraser M, Robertson N, Broadley S, Jaer M, Clayton D, Goodfellow P, Sawcer S, Compston A: The genetics of MS: The United Kingdom sibpair analysis: Principles and analysis. Brain 1998;121:1869–1887.
  22. Li YJ, Scott WK, Hedges DJ, Zhang F, Gaskell PC, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Allen FA Jr, Goetz CG, Mastaglia F, Stajich JM, Gibson RA, Middleton LT, Saunders AM, Scott BL, Small GW, Nicodemus KK, Reed AD, Schmechel DE, Welsh-Bohmer KA, Conneally PM, Roses AD, Gilbert JR, Vance JM, Haines JL, Pericak-Vance MA: Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 2002;7:985–993.
  23. Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE: Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science 2000;290:2302–2303.
  24. Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE; NIMH Genetics Initiative Alzheimer’s Disease Study Group: Results of a high-resolution genome screen of 437 Alzheimer’s disease families. Hum Mol Genet 2003;12:23–32.
  25. Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD, Baldwin CT: Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community. Hum Mol Genet 2003;12:415–422.

 goto top of outline Author Contacts

John Hardy, PhD
Laboratory of Neurogenetics, National Institute on Aging
National Institutes of Health, Building 35, Room 1A1015, MSC3707
Convent Drive, Bethesda, MD 20892-3707 (USA)
Tel. +1 301 480 6076, Fax +1 301 480 0335, E-Mail hardyj@mail.nih.gov


 goto top of outline Article Information

Number of Print Pages : 5
Number of Figures : 0, Number of Tables : 1, Number of References : 25


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 1, No. 4-5, Year 2004 (Cover Date: Released November 2004)

Journal Editor: R.M. Nitsch, Zürich; C. Hock, Zürich
ISSN: 1660–2854 (print), 1660–2862 (Online)

For additional information: http://www.karger.com/ndd


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

The identification of the apolipoprotein E gene as a risk factor for late-onset Alzheimer’s disease was a spectacularly successful application of genetic analysis to a complex trait, and it led to the hope and expectation that other risk loci for the disease would soon be forthcoming. Twelve years later, despite a huge amount of work, no other loci have been identified. In this article, we discuss the complexity of the problem and the pitfalls in the analytical methods that have been used and how we are approaching this problem.



 goto top of outline Author Contacts

John Hardy, PhD
Laboratory of Neurogenetics, National Institute on Aging
National Institutes of Health, Building 35, Room 1A1015, MSC3707
Convent Drive, Bethesda, MD 20892-3707 (USA)
Tel. +1 301 480 6076, Fax +1 301 480 0335, E-Mail hardyj@mail.nih.gov


 goto top of outline Article Information

Number of Print Pages : 5
Number of Figures : 0, Number of Tables : 1, Number of References : 25


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 1, No. 4-5, Year 2004 (Cover Date: Released November 2004)

Journal Editor: R.M. Nitsch, Zürich; C. Hock, Zürich
ISSN: 1660–2854 (print), 1660–2862 (Online)

For additional information: http://www.karger.com/ndd


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Goate AM, Chartier-Harlin MC, Mullan MC, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor MN, Owen M, Hardy J: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991;349:704–706.
  2. Sherrington R, Rogaev EL, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HAR, Haines JL, Pericak Vance M, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George Hyslop PH: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754–760.
  3. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al: Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995;269:973–977.
  4. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al: 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 1995;376:775–778.
  5. Hardy J: Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 1997;20:154–159.
  6. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;13:921–923.
  7. Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V, et al: Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer’s disease: Analysis of the 19q13.2 chromosomal region. Hum Mol Genet 1994;3:569–574.
  8. Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, et al: Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 1999;96:15233–15238.
  9. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G: Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439–1443.
  10. Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmidt SD, et al: A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 2001;8:890–899.
  11. Lucotte G, Visvikis S, Leininger-Muler B, David F, Berriche S, Reveilleau S, Couderc R, Babron MC, Aguillon D, Siest G: Association of apolipoprotein E allele epsilon 4 with late-onset sporadic Alzheimer’s disease. Am J Med Genet 1994;54:286–288.
  12. Henderson AS, Easteal S, Jorm AF, Mackinnon AJ, Korten AE, Christensen H, Croft L, Jacomb PA: Apolipoprotein E allele epsilon 4, dementia, and cognitive decline in a population sample. Lancet 1995;346:1387–1390.
  13. Ritchie K, Kotzki PO, Touchon J, Cristol JP: Characteristics of Alzheimer’s disease patients with and without ApoE4 allele. Lancet 1996;348:960.
  14. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM: 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. Ann Neurol 1995;38:797–808.
  15. Daw EW, Heath SC, Wijsman EM: Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer disease pedigrees. Am J Hum Genet 1999;64:839–851.
  16. Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE, Perry RT, Bassett SS, Chase G, Meyers D, Albert MS, Tanzi R: ApoE-4 and age at onset of Alzheimer’s disease: The NIMH genetics initiative. Neurology 1997;48:139–147.
  17. Kehoe P, Wavrant-De Vrieze F, Crook R, Wu WS, Holmans P, Fenton I, Spurlock G, Norton N, Williams H, Williams N, Lovestone S, Pérez-Tur J, Hutton M, Chartier-Harlin MC, Shears S, Roehl K, Booth J, Van Voorst W, Ramic D, Williams J, Goate A, Hardy J, Owen MJ: A full genome scan for late onset Alzheimer’s disease. Hum Mol Genet 1999;8:237–245.
  18. Myers A, Wavrant-De Vrieze F, Holmans P, Hamshere M, Crook R, Compton D, Marshall H, Meyer D, Shears S, Booth J, Ramic D, Knowles H, Morris JC, Williams N, Norton N, Abraham R, Kehoe P, Williams H, Rudrasingham V, Rice F, Giles P, Tunstall N, Jones L, Lovestone S, Williams J, Owen MJ, Hardy J, Goate A: Full genome screen for Alzheimer disease: Stage II analysis. Am J Med Genet 2002;114:235–244.
  19. Pericak-Vance MA, Grubber J, Bailey LR, Hedges D, West S, Santoro L, Kemmerer B, Hall JL, Saunders AM, Roses AD, Small GW, Scott WK, Conneally PM, Vance JM, Haines JL: Identification of novel genes in late-onset Alzheimer’s disease. Exp Gerontol 2000;35:1343–1352.
  20. Romas SN, Santana V, Williamson J, Ciappa A, Lee JH, Rondon HZ, Estevez P, Lantigua R, Medrano M, Torres M, Stern Y, Tycko B, Mayeux R: Familial Alzheimer disease among Caribbean Hispanics: A reexamination of its association with APOE. Arch Neurol 2002;59:87–91.
  21. Chataway J, Feakes R, Coraddu F, Gray J, Dea J, Fraser M, Robertson N, Broadley S, Jaer M, Clayton D, Goodfellow P, Sawcer S, Compston A: The genetics of MS: The United Kingdom sibpair analysis: Principles and analysis. Brain 1998;121:1869–1887.
  22. Li YJ, Scott WK, Hedges DJ, Zhang F, Gaskell PC, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Allen FA Jr, Goetz CG, Mastaglia F, Stajich JM, Gibson RA, Middleton LT, Saunders AM, Scott BL, Small GW, Nicodemus KK, Reed AD, Schmechel DE, Welsh-Bohmer KA, Conneally PM, Roses AD, Gilbert JR, Vance JM, Haines JL, Pericak-Vance MA: Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 2002;7:985–993.
  23. Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE: Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science 2000;290:2302–2303.
  24. Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE; NIMH Genetics Initiative Alzheimer’s Disease Study Group: Results of a high-resolution genome screen of 437 Alzheimer’s disease families. Hum Mol Genet 2003;12:23–32.
  25. Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD, Baldwin CT: Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community. Hum Mol Genet 2003;12:415–422.