Identification of Genes that Modify the Age of Onset in a Large Familial Alzheimer's Disease Kindred

  • Alison M. Goate
  • Pau Pastor
  • Catherine M. Roe
  • Joanne Norton
  • Sumi Chakraverty
  • Francisco Lopera
  • Kenneth S. Kosik
Conference paper
Part of the Research and Perspectives in Alzheimer's Disease book series (ALZHEIMER)


We have identified more than 20 nuclear Alzheimer's disease (AD) families in Colombia that carry a single point mutation, E280A, in the presenilin 1 (PSEN1) gene. Genealogical and genetic studies have demonstrated that these families share a common founder more than 400 years ago. The mean age of onset of AD in these families is 45.2 years but the range is almost 30 years (35–62 years). The wide range in age of onset suggests that genetic and/or environmental risk factors modify the age of onset. We are using two complementary approaches to the identification of genetic modifiers: candidate gene analyses and a whole genome screen analysis.

We have genotyped polymorphisms in each of the known AD genes: ß-amyloid protein precursor gene (APP), presenilin 1 (PSEN1) gene, presenilin 2 (PSEN2) gene and apolipoprotein E gene (APOE). Several polymorphisms in these genes have previously been associated with risk for AD in some but not all studies. To determine whether these polymorphisms modify the age of onset in the Colombian kindreds, we initially used survival curve analysis. The only gene that modified age of onset with this methodology was APOE. The APOE4 allele was associated with an earlier age of onset whereas the presence of the APOE2 allele was associated with later age of onset. This result is consistent with the observations of the effect of APOE alleles on sporadic AD and suggests that genes that influence the risk for late onset AD may also modify age of onset in familial early onset Alzheimer's disease (FAD).

We have also used survival analysis to examine several putative environmental risk factors. These studies demonstrated that both years of education and urban dwelling were associated with an earlier age of onset. Since these two factors were highly correlated in this study, it was not possible to determine which one was primarily the responsible risk factor.

To identify novel genetic risk factors for AD, we have used two complementary approaches: genetic analysis of a large series of late onset AD sibling pairs and a search for genes that modify age of onset in the Colombian families. Our genome screen in AD sibling pairs has provided evidence of AD susceptibility genes on chromosomes 9, 10, and 12 and suggestive evidence of an age of onset modifier gene on chromosome 12.


Cerebral Amyloid Angiopathy PSEN1 Mutation PSEN2 Gene Colombian Family E280A PSEN1 Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Antonelli IR, Marra C, Gemma A, Capparella O, Carbonin PU (1992) Unrecognized dementia: sociodemographic correlates. Aging Clin Exp Res 4: 327–332.Google Scholar
  2. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS (1996) Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta 1-42/1-40 ratio in vitro and in vivo. Neuron 17:1005–1013.CrossRefPubMedGoogle Scholar
  3. Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V, Fruchart J-C, Delacourte A, Rossor M, Amouyel P (1994) 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 3:569–574.PubMedGoogle Scholar
  4. Corbo RM, Scacchi R (1999) Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele? Ann Hum Genet 63 ( Pt 4):301–310.CrossRefPubMedGoogle Scholar
  5. 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 261:921–923.PubMedGoogle Scholar
  6. Cornejo W, Lopera F, Uribe CS, Salinas M (1987) Descripción de una familia con demencia presenil tipo Alzheimer. Acta Med Colombiana 12:55–61.Google Scholar
  7. Daw EW, Heath SC, Wijsman EM (1999) Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer disease pedigrees. Am J Hum Genet 64:839–851.CrossRefPubMedGoogle Scholar
  8. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rook, K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704–706.CrossRefPubMedGoogle Scholar
  9. Graff-Radford NR, Green RC, Go RC, Hutton ML, Edeki T, Bachman D, Adamson JL, Griffith P, Willis FB, Williams M, Hipps Y, Haines JL, Cupples LA, Farrer LA (2002) Association between apolipoprotein E genotype and Alzheimer disease in African American subjects. Arch Neurol 59:594–600.CrossRefPubMedGoogle Scholar
  10. Haan J, Van Broeckhoven C, van Duijn CM, Voorhoeve E, van Harskamp F, van Swieten JC, Maat-Schieman ML, Roos RA, Bakker E (1994) The apolipoprotein E epsilon 4 allele does not influence the clinical expression of the amyloid precursor protein gene codon 693 or 692 mutations. Ann Neurol 36:434–437.CrossRefPubMedGoogle Scholar
  11. Henderson AS, Easteal S, Jorm AF, Mackinnon AJ, Korten AE, Christensen H, Croft L, Jacomb PA (1995) Apolipoprotein E allele epsilon 4, dementia, and cognitive decline in a population sample. Lancet 346:1387–1390.CrossRefPubMedGoogle Scholar
  12. Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, Bales K, Ashe KH, Irizarry MC, Hyman BT (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model. Ann Neurol 47:739–747.CrossRefPubMedGoogle Scholar
  13. Kovacs DM, Fausett HJ, Page KJ, Kim TW, Moir RD, Merriam DE, Hollister RD, Hallmark OG, Mancini R, Felsenstein KM, Hyman BT, Tanzi RE, Wasco W (1996) Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat Med 2:224–229.CrossRefPubMedGoogle Scholar
  14. Kukull WA, Schellenberg GD, Bowen JD, McCormick WC, Yu CE, Teri L, Thompson JD, O'Meara ES, Larson EB (1996) Apolipoprotein E in Alzheimer's disease risk and case detection: a casecontrol study. J Clin Epidemiol 49:1143–1148.CrossRefPubMedGoogle Scholar
  15. Lendon CL, Martinez A, Behrens IM, Kosik KS, Madrigal L, Norton J, Neuman R, Myers A, Busfield F, Wragg M, Arcos M, Arango Viana JC, Ossa J, Ruiz A, Goate AM, Lopera F (1997) E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat 10:186–195.CrossRefPubMedGoogle Scholar
  16. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC; Fu YH, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269:973–977.PubMedGoogle Scholar
  17. 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 (2002) Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 70:985–993.CrossRefPubMedGoogle Scholar
  18. Li Y, Nowotny P, Holmans P, Smemo S, Kauwe J, Tacey K, Doil L, van Luchen R, Garcia V, Rowland C, Schrodi S, Leong D, Gogic G, Chan J, Cravchik A, Ross D, Lau K, Kwok S, Chang S-Y, Catanes J, Sninsky J, White T, Hardy J, Powell J, Lovestone S, Thal L, Owen M, Williams J, Goate A, Grupe A (2004) Association of late onset Alzheimer's disease with genetic variation in multiple members of the glyceraldehyde-3-phosphate dehydrogenase gene family. Proc. Natn. Acad. Sci. USA 101:15688–15693CrossRefGoogle Scholar
  19. Lopera F, Arcos-Burgos M, Madrigal L, Kosik KS, Cornejo W, Ossa J (1994) Demencia tipo Alzheimer con Agregación familiar en Antioquia, Colombia. Acta Neurológica Colombiana 10:173–187.Google Scholar
  20. Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240:622–630.PubMedGoogle Scholar
  21. Martins RN, Clarnette R, Fisher C, Broe GA, Brooks WS, Montgomery P, Gandy SE (1995) ApoE genotypes in Australia: roles in early and late onset Alzheimer's disease and Down's syndrome. Neuroreport 6:1513–1516.PubMedGoogle Scholar
  22. Meyer MR, Tschanz JT, Norton MC, Welsh-Bohmer KA, Steffens DC, Wyse BW, Breitner JC (1998) APOE genotype predicts when-not whether-one is predisposed to develop Alzheimer disease. Nat Genet 19:321–322.CrossRefPubMedGoogle Scholar
  23. Olichney JM, Hansen LA, Galasko D, Saitoh T, Hofstetter CR, Katzman R, Thal LJ (1996) The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant. Neurology 47:190–196.PubMedGoogle Scholar
  24. Pastor P, Roe CM, Villegas A, Bedoya G, Chakraverty S, Garcia G, Tirado V, Norton J, Rios S, Martinez M, Kosik KS, Lopera F, Goate AM (2003) Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol 54:163–169.CrossRefPubMedGoogle Scholar
  25. 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 (2000) Identification of novel genes in late-onset Alzheimer's disease. Exp Gerontol 35:1343–1352.CrossRefPubMedGoogle Scholar
  26. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993) Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342:697–699.CrossRefPubMedGoogle Scholar
  27. Riazanskaia N, Lukiw WJ, Grigorenko A, Korovaitseva G, Dvoryanchikov G, Moliaka Y, Nicolaou M, Farrer L, Bazan NG, Rogaev E (2002) Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD. Mol Psychiatry 7:891–898.CrossRefPubMedGoogle Scholar
  28. Rosenberg RN (2000) The molecular and genetic basis of AD: the end of the beginning: the 2000 Wartenberg lecture. Neurology 54:2045–2054.PubMedGoogle Scholar
  29. Scott WK, Hauser ER, Schmechel DE, Welsh-Bohmer KA, Small GW, Roses AD, Saunders AM, Gilbert JR, Vance JM, Haines JL, Pericak-Vance MA (2003) Ordered-subsets linkage analysis detects novel Alzheimer disease Loci on chromosomes 2q34 and 15q22. Am J Hum Genet 73:1041–1051.CrossRefPubMedGoogle Scholar
  30. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin J-F, 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 MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375:754–760.CrossRefPubMedGoogle Scholar
  31. Sorbi S, Nacmias B, Forleo P, Piacentini S, Latorraca S, Amaducci L (1995) Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease. Ann Neurol 38:124–127.CrossRefPubMedGoogle Scholar
  32. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (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 U S A 90:1977–1981.PubMedGoogle Scholar
  33. Tang MX, Stern Y, Marder K, Bell K, Gurland B, Lantigua R, Andrews H, Feng L, Tycko B, Mayeux R (1998) The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. Jama 279:751–755.CrossRefPubMedGoogle Scholar
  34. Theuns J, Del-Favero J, Dermaut B, van Duijn CM, Backhovens H, Van den Broeck MV, Serneels S, Corsmit E, Van Broeckhoven CV, Cruts M (2000) Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression. Hum Mol Genet 9:325–331.CrossRefPubMedGoogle Scholar
  35. Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL, Borchelt DR, Sisodia SS (1997) Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 272:28415–28422.CrossRefPubMedGoogle Scholar
  36. Tsai MS, Tangalos EG, Petersen RC, Smith GE, Schaid DJ, Kokmen E, Ivnik RJ, Thibodeau SN (1994) Apolipoprotein E: risk factor for Alzheimer disease. Am J Hum Genet 54:643–649.PubMedGoogle Scholar
  37. Van Broeckhoven C, Backhovens H, Cruts M, Martin JJ, Crook R, Houlden H, Hardy J (1994) APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease. Neurosci Lett 169:179–180.CrossRefPubMedGoogle Scholar
  38. Walker ES, Martinez M, Brunkan AL, Goate A (2005) Presenilin 2 familial Alzheimer's disease mutations result in partial loss of functin and dramatic changes in Abeta 42/40 ratios. J Neurochem 92:294–301.CrossRefPubMedGoogle Scholar
  39. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513–517.CrossRefPubMedGoogle Scholar
  40. Zannis VI, Just PW, Breslow JL (1981) Human apolipoprotein E isoprotein subclasses are genetically determined. Am J Hum Genet 33:11–24.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • Alison M. Goate
    • 1
    • 2
  • Pau Pastor
    • 1
  • Catherine M. Roe
    • 3
  • Joanne Norton
    • 1
  • Sumi Chakraverty
    • 1
  • Francisco Lopera
    • 4
  • Kenneth S. Kosik
    • 5
  1. 1.Department of PsychiatryWashington University School of MedicineSt. Louis
  2. 2.Department of PsychiatryWashington University School of MedicineSt. Louis
  3. 3.Division of Biostatistics, and Alzheimer's Disease Research CenterWashington University School of MedicineSt. Louis
  4. 4.Grupo de Neurociencias. Facultad de MedicinaUniversidad de AntioquíaMedellínColombia
  5. 5.Center for Neurological Diseases, Harvard Medical SchoolBrigham and Women's HospitalBoston

Personalised recommendations