, Volume 5, Issue 4, pp 209–213 | Cite as

Apolipoprotein E is associated with age at onset of amyotrophic lateral sclerosis

  • Yi-Ju Li
  • Margaret A. Pericak-Vance
  • Jonathan L. Haines
  • Nailah Siddique
  • Diane McKenna-Yasek
  • Wu-Yen Hung
  • Peter Sapp
  • Coy I. Allen
  • Wenjie Chen
  • Betsy Hosler
  • Ann M. Saunders
  • Lisa M. Dellefave
  • Robert H. BrownJr
  • Teepu Siddique
Original Article


Apolipoprotein E (APOE) is a confirmed risk factor for Alzheimer disease. APOE is also involved in several other neurodegenerative disorders, including Parkinson disease and multiple sclerosis. Previous studies of amyotrophic lateral sclerosis (Lou Gehrig disease, ALS) have investigated the effect of APOE on the risk of developing ALS, age at onset, site of onset, and duration of the disease. The results have been inconsistent, possibly due to small sample sizes and complete reliance on case-control data. No family-based association studies were performed. To address these limitations, we investigated the relationship between APOE functional polymorphisms and age at onset of ALS in a large set of 508 families. We treated age at onset as a quantitative trait and performed family-based association analysis using the TDT Q5 method. APOE-2 is protective against earlier onset ( P =0.001) with an average age at onset of APOE-2 carriers approximately 3 years later than that of non-APOE-2 carriers. Similar to our previous report, we did not find APOE associated with ALS risk. Our findings suggest that APOE may express its strongest effect through age at onset rather than on risk.


Amyotrophic lateral sclerosis Apolipoprotein E Age at onset Association Quantitative trait 



We would like to thank the families and patients with ALS for their participation in this study. Without their help this work would not have been possible. This research was supported by the National Institute of Neurological Disorders and Stroke (NS 37912, NS021442), Les Turner ALS Foundation, Vena E. Schaff ALS Research Fund, Harold Post Research Professorship, Herbert and Florence C. Wenske Foundation, Ralph and Marian Falk Medical Research Trust, Abbott Labs Duane, and Susan Burnham Professorship. R.H.’s laboratory also receives support for this work from the NINDS, the NIA, project ALS, the Angel Fund, the ALS Association, and the Al-Athel ALS Research Foundation. P.S. is supported through the laboratory of H.R. Horvitz, an investigator of the Howard Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Mass.


  1. 1.
    Siddique T, Figlewicz DA, Pericak-Vance MA, Haines JL, Rouleau G, Jeffers AJ, Sapp P, Hung WY, Bebout J, McKenna-Yasek D, Deng G, Horvitz HR, Gusella JF, Brown RH Jr, Roses AD (1991) Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med 324:1381–1384PubMedGoogle Scholar
  2. 2.
    Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston SM, Berger R, Tanzi RE, Halperin JJ, Herzfeldt B, Van den Bergh R, Hung WY, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak-Vance MA, Haines J, Rouleau GA, Gusella J, Horvitz HR, Brown RH Jr (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62CrossRefPubMedGoogle Scholar
  3. 3.
    Hentati A, Bejaoui K, Pericak-Vance MA, Hentati F, Speer MC, Hung WY, Figlewicz DA, Haines J, Rimmler J, Ben Hamida C, Ben Hamida M, Brown RHJ, Siddique T (1994) Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet 7:425–428CrossRefPubMedGoogle Scholar
  4. 4.
    Hosler BA, Sapp PC, Berger R, O’Neill G, Bejaoui K, Hamida MB, Hentati F, Chin W, McKenna-Yasek D, Haines JL, Patterson D, Horvitz HR, Brown RH Jr, Day CB (1998) Refined mapping and characterization of the recessive familial amyotrophic lateral sclerosis locus ( ALS2) on chromosome 2q33. Neurogenetics 2:34–42CrossRefPubMedGoogle Scholar
  5. 5.
    Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain A, Daube JR, Nance M, Fan C, Kaplan J, Hung WY, McKenna-Yasek D, Haines JL, Pericak-Vance MA, Horvitz HR, Brown RH Jr (2000) Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 284:1664–1669CrossRefPubMedGoogle Scholar
  6. 6.
    Hentati A, Ouahchi K, Pericak-Vance MA, Nijhawan D, Ahmad A, Yi Y, Rimmler J, Hung WY, Schlotter B, Ahmed A, Ben Hamida M, Hentati F, Siddique T (1998) Linkage of a common locus for recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 2:55–60CrossRefPubMedGoogle Scholar
  7. 7.
    Abalkhail H, Mitchell J, Habgood J, Orrell R, Belleroche J de (2003) A new familial amyotrophic lateral sclerosis locus on chromosome 16q12.1–16q12.2. Am J Hum Genet 73:383–389CrossRefPubMedGoogle Scholar
  8. 8.
    Sapp PC, Hosler BA, McKenna-Yasek D, Chin W, Gann A, Genise H, Gorenstein J, Huang M, Sailer W, Scheffler M, Valesky M, Haines JL, Pericak-Vance M, Siddique T, Horvitz HR, Brown RH Jr (2003) Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet 73:397–403CrossRefPubMedGoogle Scholar
  9. 9.
    Ruddy DM, Parton MJ, Al Chalabi A, Lewis CM, Vance C, Smith BN, Leigh PN, Powell JF, Siddique T, Meyjes EP, Baas F, Shaw CE (2003) Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. Am J Hum Genet 73:390–396CrossRefPubMedGoogle Scholar
  10. 10.
    Hand CK, Khoris J, Salachas F, Gros-Louis F, Lopes AAS, Mayeux PV, Brown RH, Meininger V, Camu W, Rouleau GA (2002) A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am J Hum Genet 70:251–256CrossRefPubMedGoogle Scholar
  11. 11.
    Siddique T, Hong S-T, Brooks BR, Hung WY, Siddique NA, Rimmler J, Kaplan JP, Haines JL, Brown RH Jr, Pericak-Vance MA (2004) X-linked dominant locus for late-onset familial amyotrophic lateral sclerosis. Am J Hum Genet:A308Google Scholar
  12. 12.
    Pericak-Vance MA, St George-Hyslop PH, Gaskell PC Jr, Growdon J, Crain BJ, Hulette C, Gusella JF, Yamaoka L, Tanzi RE, Roses AD, Haines JL (1993) Linkage analysis in familial Alzheimer disease: description of the Duke and Boston data sets. Genet Epidemiol 10:361–364PubMedGoogle Scholar
  13. 13.
    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 261:921–923PubMedGoogle Scholar
  14. 14.
    Zareparsi S, Kaye J, Camicioli R, Grimslid H, Oken B, Litt M, Nutt J, Bird T, Schellenberg G, Payami H (1997) Modulation of the age at onset of Parkinson’s disease by apolipoprotein E genotypes. Ann Neurol 42:655–658PubMedGoogle Scholar
  15. 15.
    Li YJ, Hauser MA, Scott WK, Martin ER, Booze MW, Qin XJ, Walter JW, Nance MA, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner CB, Jankovic J, Goetz CG, Small GW, Mastaglia F, Haines JL, Pericak-Vance MA, Vance JA (2004) Apolipoprotein E controls the risk and age at onset of Parkinson Disease. Neurology 62:2005–2009PubMedGoogle Scholar
  16. 16.
    Mui S, Rebeck GW, McKenna-Yasek D, Hyman BT, Brown RH Jr (1995) Apolipoprotein E epsilon 4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis. Ann Neurol 38:460–463PubMedGoogle Scholar
  17. 17.
    Siddique T, Pericak-Vance MA, Caliendo J, Hong ST, Hung WY, Kaplan J, McKenna-Yasek D, Rimmler JB, Sapp P, Saunders AM, Scott WK, Siddique N, Haines JL, Brown RH (1998) Lack of association between apolipoprotein E (APOE) genotype and sporadic amyotrophic lateral sclerosis (ALS). Neurogenetics 1:213–216CrossRefPubMedGoogle Scholar
  18. 18.
    Bachus R, Bader S, Gessner R, Ludolph AC (1997) Lack of association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease. Ann Neurol 41:417PubMedGoogle Scholar
  19. 19.
    Moulard B, Sefiani A, Laamri A, Malafosse A, Camu W (1996) Apolipoprotein E genotyping in sporadic amyotrophic lateral sclerosis: evidence for a major influence on the clinical presentation and prognosis. J Neurol Sci 139 [Suppl]:34–37Google Scholar
  20. 20.
    Drory VE, Birnbaum M, Korczyn AD, Chapman J (2001) Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis. J Neurol Sci 190:17–20CrossRefPubMedGoogle Scholar
  21. 21.
    Al-Chalabi A, Enayat ZE, Bakker MC, Sham PC, Ball DM, Shaw CE, Lloyd CM, et al (1996) Association of apolipoprotein E ε4 allele with bulbar-onset motor neuron disease. Lancet 347:159–160CrossRefPubMedGoogle Scholar
  22. 22.
    Smith RG, Haverkamp LJ, Case S, Appel V, Appel SH (1996) Apolipoprotein E epsilon 4 in bulbar-onset motor neuron disease. Lancet 348:334–335Google Scholar
  23. 23.
    Wilbourn AJ (1998) Clinical neurophysiology in the diagnosis of amyotrophic lateral sclerosis: the Lambert and the El Escorial criteria. J Neurol Sci 160 [Suppl 1]:S25–S29Google Scholar
  24. 24.
    Vance JM (1998) The collection of biological samples for DNA analysis. In: Haines JL, Pericak-Vance MA (eds) Approaches to gene mapping in complex human diseases. Wiley-Liss, New YorkGoogle Scholar
  25. 25.
    Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472PubMedGoogle Scholar
  26. 26.
    Rimmler JB, Haynes CS, McDowell JG, Stajich JE, Adams CS, Slotterbeck BD, Rogala AR, West SG, Gilbert JR, Hauser ER, Vance JM, Pericak-Vance MA (1999) DataTracker: comprehensive software for data quality control protocols in complex disease studies. Am J Hum Genet 65 [Suppl]:A442Google Scholar
  27. 27.
    Haynes C, Speer MC, Peedin M, Roses AD, Haines JL, Vance JM, Pericak-Vance MA (1995) PEDIGENE: a comprehensive data management system to facilitate efficient and rapid disease gene mapping. Am J Hum Genet 57:A193Google Scholar
  28. 28.
    O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266CrossRefPubMedGoogle Scholar
  29. 29.
    Zaykin D, Zhivotovsky L, Weir BS (1995) Exact tests for association between alleles at arbitrary numbers of loci. Genetica 96:169–178PubMedGoogle Scholar
  30. 30.
    Allison DB (1997) Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet 60:676–690PubMedGoogle Scholar
  31. 31.
    Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292CrossRefPubMedGoogle Scholar
  32. 32.
    Rabinowitz D (1997) A transmission disequilibrium test for quantitative trait loci. Hum Hered 47:342–350PubMedGoogle Scholar
  33. 33.
    Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 67:146–154CrossRefPubMedGoogle Scholar
  34. 34.
    Martin ER, Bass MP, Kaplan NL (2001) Correcting for a potential bias in the pedigree disequilibrium test. Am J Hum Gen 68:1065–1067CrossRefPubMedGoogle Scholar
  35. 35.
    Martin ER, Bass MP, Pericak-Vance MA, Hauser ER (2003) Genotype-based associtation test for general pedigrees: the genotype-PDT. Genet Epidemiol 25:203–213CrossRefPubMedGoogle Scholar
  36. 36.
    Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln RR, Bucher P, Saunders AM, Lai E, Martin ER, Vance JM, Oksenberg JR, Hauser SL, Pericak-Vance MA, Haines JL, Multiple Sclerosis GG (2002) Association of polymorphisms in the apolipoprotein e region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet 70:708–717CrossRefPubMedGoogle Scholar
  37. 37.
    Li CC (1972) Populations subdivision with respect to multiple alleles. Ann Hum Genet 33:23–29Google Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Yi-Ju Li
    • 1
    • 7
  • Margaret A. Pericak-Vance
    • 1
  • Jonathan L. Haines
    • 2
  • Nailah Siddique
    • 3
  • Diane McKenna-Yasek
    • 4
  • Wu-Yen Hung
    • 3
  • Peter Sapp
    • 4
    • 5
  • Coy I. Allen
    • 1
  • Wenjie Chen
    • 3
  • Betsy Hosler
    • 4
  • Ann M. Saunders
    • 6
  • Lisa M. Dellefave
    • 3
  • Robert H. BrownJr
    • 4
  • Teepu Siddique
    • 3
  1. 1.Center for Human Genetics, Department of MedicineDuke University Medical CenterDurhamUSA
  2. 2.Center for Human Genetics ResearchVanderbilt University Medical CenterNashvilleUSA
  3. 3.Department of NeurologyNorthwestern University Feinberg School of Medicine and Northwestern University Institute of NeuroscienceChicagoUSA
  4. 4.Day Neuromuscular LaboratoryMassachusetts General HospitalCharlestownUSA
  5. 5.Howard Hughes Medical Institute, Department of BiologyMassachusetts Institute of TechnologyCambridgeUSA
  6. 6.Department of Medicine, Division of NeurologyDuke University Medical CenterDurhamUSA
  7. 7.Center for Human GeneticsDuke University Medical CenterDurhamUSA

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