Skip to main content

Advertisement

SpringerLink
Log in

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

  • Original Article
  • Published:
Neurogenetics Aims and scope Submit manuscript

Abstract

The aim of the study was to identify chromosomal regions that may harbor putative genetic variants influencing age at onset in familial late-onset Alzheimer’s disease (LOAD). Data from a genome-wide scan that included genotyping of APOE were analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age at onset of 73.3 years multiply affected by LOAD. Two-point and multipoint analyses were conducted using variance component methods using 376 microsatellite markers with an average intermarker distance of 9.3 cM. Family-based test of association was also conducted for the same set of markers. Age at onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-ɛ4 lowered the age at onset by 3 years. Several candidate loci were identified. Using linkage analysis strategy, the highest logarithm of odds (LOD) scores were obtained using a conservative definition of LOAD at 5q15 (LOD = 3.1), 17q25.1 (LOD = 2.94), 14q32.12 (LOD = 2.36), and 7q36.3 (LOD = 2.29) in a model that adjusted for APOE-ɛ4 and other covariates. Both linkage and family-based association identified 17p13 as a candidate region. Family-based association analysis showed markers at 12q13 (p = 0.00002), 13q33 (p = 0.00043), and 14q23 (p = 0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age at onset of late onset Alzheimer’s disease. The novel loci at 5q15, 17q25.1, 13q33, and 17p13 and the previously reported loci at 7q36.3, 12q13, 14q23, and 14q32 need further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Nussbaum RL, Ellis CE (2003) Alzheimer’s disease and Parkinson’s disease. N Engl J Med 348:1356–1364

    Article  PubMed  CAS  Google Scholar 

  2. St George-Hyslop PH, Petit A (2005) Molecular biology and genetics of Alzheimer’s disease. C R Biol 328:119–130

    Article  PubMed  CAS  Google Scholar 

  3. Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120:545–555

    Article  PubMed  CAS  Google Scholar 

  4. Pastor P, Goate AM (2004) Molecular genetics of Alzheimer’s disease. Curr Psychiatry Rep 6:125–133

    Article  PubMed  Google Scholar 

  5. Lander ES, Schork NJ (1994) Genetic dissection of complex traits, vol 265. Science, New York, NY, pp 2037–2048

    Google Scholar 

  6. Kamboh MI (2004) Molecular genetics of late-onset Alzheimer’s disease. Ann Hum Genet 68:381–404

    Article  PubMed  CAS  Google Scholar 

  7. Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE et al (1997) ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology 48:139–147

    PubMed  CAS  Google Scholar 

  8. Breitner JC, Jarvik GP, Plassman BL, Saunders AM, Welsh KA (1998) Risk of Alzheimer disease with the epsilon4 allele for apolipoprotein E in a population-based study of men aged 62–73 years. Alzheimer Dis Assoc Disord 12:40–44

    Article  PubMed  CAS  Google Scholar 

  9. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families, vol 261. Science, New York, NY, pp 921–923

    Google Scholar 

  10. Harwood DG, Barker WW, Ownby RL, St George-Hyslop P, Mullan M, Duara R (2004) Apolipoprotein E polymorphism and age of onset for Alzheimer’s disease in a bi-ethnic sample. Int Psychogeriatr 16:317–326

    Article  PubMed  Google Scholar 

  11. Nicodemus KK, Stenger JE, Schmechel DE, Welsh-Bohmer KA, Saunders AM, Roses AD et al (2004) Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease. Neurogenetics 5:201–208

    Article  PubMed  CAS  Google Scholar 

  12. Wijsman EM, Daw EW, Yu X, Steinbart EJ, Nochlin D, Bird TD et al (2005) APOE and other loci affect age-at-onset in Alzheimer’s disease families with PS2 mutation. Am J Med Genet B Neuropsychiatr Genet 132:14–20

    PubMed  Google Scholar 

  13. Daw EW, Payami H, Nemens EJ, Nochlin D, Bird TD, Schellenberg GD et al (2000) The number of trait loci in late-onset Alzheimer disease. Am J Hum Genet 66:196–204

    Article  PubMed  CAS  Google Scholar 

  14. Holmans P, Hamshere M, Hollingworth P, Rice F, Tunstall N, Jones S et al (2005) Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 135:24–32

    PubMed  Google Scholar 

  15. Li YJ, Scott WK, Hedges DJ, Zhang F, Gaskell PC, Nance MA et al (2002) Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 70:985–993

    Article  PubMed  CAS  Google Scholar 

  16. Nacmias B, Latorraca S, Piersanti P, Forleo P, Piacentini S, Bracco L et al (1995) ApoE genotype and familial Alzheimer’s disease: a possible influence on age of onset in APP717 Val–>Ile mutated families. Neurosci Lett 183:1–3

    Article  PubMed  CAS  Google Scholar 

  17. Olson JM, Goddard KA, Dudek DM (2002) A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20 p and epistasis between 20 p and the amyloid precursor protein region. Am J Hum Genet 71:154–161

    Article  PubMed  CAS  Google Scholar 

  18. Rademakers R, Cruts M, Sleegers K, Dermaut B, Theuns J, Aulchenko Y et al (2005) Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample. Am J Hum Genet 77:643–652

    Article  PubMed  CAS  Google Scholar 

  19. Wavrant-De Vrieze F, Crook R, Holmans P, Kehoe P, Owen MJ, Williams J et al (1999) Genetic variability at the amyloid-beta precursor protein locus may contribute to the risk of late-onset Alzheimer’s disease. Neurosci Lett 269:67–70

    Article  PubMed  Google Scholar 

  20. Wijsman EM, Daw EW, Yu CE, Payami H, Steinbart EJ, Nochlin D et al (2004) Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2. Am J Hum Genet 75:398–409

    Article  PubMed  CAS  Google Scholar 

  21. Lee JH, Cheng R, Santana V, Williamson J, Lantigua R, Medrano M et al (2006) Expanded genomewide scan implicates a novel locus at 3q28 among Caribbean hispanics with familial Alzheimer disease. Arch Neurol 63:1591–1598

    Article  PubMed  Google Scholar 

  22. Lee JH, Mayeux R, Mayo D, Mo J, Santana V, Williamson J et al (2004) Fine mapping of 10q and 18q for familial Alzheimer’s disease in Caribbean Hispanics. Mol Psychiatry 9:1042–1051

    Article  PubMed  CAS  Google Scholar 

  23. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) 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 34:939–944

    PubMed  CAS  Google Scholar 

  24. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572

    Article  PubMed  CAS  Google Scholar 

  25. Pittman J, Andrews H, Tatemichi T, Link B, Struening E, Stern Y et al (1992) Diagnosis of dementia in a heterogeneous population. A comparison of paradigm-based diagnosis and physician’s diagnosis. Arch Neurol 49:461–467

    PubMed  CAS  Google Scholar 

  26. Stern Y, Andrews H, Pittman J, Sano M, Tatemichi T, Lantigua R et al (1992) Diagnosis of dementia in a heterogeneous population. Development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. Arch Neurol 49:453–460

    PubMed  CAS  Google Scholar 

  27. Stricks L, Pittman J, Jacobs DM, Sano M, Stern Y (1998) Normative data for a brief neuropsychological battery administered to English- and Spanish-speaking community-dwelling elders. J Int Neuropsychol Soc 4:311–318

    PubMed  CAS  Google Scholar 

  28. Ganguli M, Dodge HH, Chen P, Belle S, DeKosky ST (2000) Ten-year incidence of dementia in a rural elderly US community population: the MoVIES Project. Neurology 54:1109–1116

    PubMed  CAS  Google Scholar 

  29. Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548

    PubMed  CAS  Google Scholar 

  30. Maestre G, Ottman R, Stern Y, Gurland B, Chun M, Tang MX et al (1995) Apolipoprotein E and Alzheimer’s disease: ethnic variation in genotypic risks. Ann Neurol 37:254–259

    Article  PubMed  CAS  Google Scholar 

  31. Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH et al (2001) A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA 286:2257–2263

    Article  PubMed  CAS  Google Scholar 

  32. Preisser JS, Koch GG (1997) Categorical data analysis in public health. Annu Rev Public Health 18:51–82

    Article  PubMed  CAS  Google Scholar 

  33. Zeger SL, Liang KY (1992) An overview of methods for the analysis of longitudinal data. Stat Med 11:1825–1839

    Article  PubMed  CAS  Google Scholar 

  34. Amos CI (1994) Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet 54:535–543

    PubMed  CAS  Google Scholar 

  35. Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211

    Article  PubMed  CAS  Google Scholar 

  36. Comuzzie AG, Williams JT (1999) Correcting for ascertainment bias in the COGA data set. Genet Epidemiol 17(Suppl 1):S109–S114

    PubMed  Google Scholar 

  37. Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971

    PubMed  CAS  Google Scholar 

  38. Doerge RW, Churchill GA (1996) Permutation tests for multiple loci affecting a quantitative character. Genetics 142:285–294

    PubMed  CAS  Google Scholar 

  39. Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 9:301–306

    Article  PubMed  CAS  Google Scholar 

  40. Rabinowitz D, Laird N (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 50:211–223

    Article  PubMed  CAS  Google Scholar 

  41. Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR et al (2003) Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet 12:3259–3267

    Article  PubMed  CAS  Google Scholar 

  42. Avramopoulos D, Fallin MD, Bassett SS (2005) Linkage to chromosome 14q in Alzheimer’s disease (AD) patients without psychotic symptoms. Am J Med Genet B Neuropsychiatr Genet 132:9–13

    PubMed  Google Scholar 

  43. Kamboh MI, Minster RL, Kenney M, Ozturk A, Desai PP, Kammerer CM et al (2006) Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer’s disease. Neurobiol Aging 27:1435–1439

    Article  PubMed  CAS  Google Scholar 

  44. Risch NJ (2000) Searching for genetic determinants in the new millennium. Nature 405:847–856

    Article  PubMed  CAS  Google Scholar 

  45. Tunstall N, Owen MJ, Williams J, Rice F, Carty S, Lillystone S et al (2000) Familial influence on variation in age of onset and behavioural phenotype in Alzheimer’s disease. Br J Psychiatry 176:156–159

    Article  PubMed  CAS  Google Scholar 

  46. Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH et al (2007) A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry 68:613–618

    Article  PubMed  CAS  Google Scholar 

  47. Goddard KA, Olson JM, Payami H, van der Voet M, Kuivaniemi H, Tromp G (2004) Evidence of linkage and association on chromosome 20 for late-onset Alzheimer disease. Neurogenetics 5:121–128

    Article  PubMed  CAS  Google Scholar 

  48. Kolsch H, Linnebank M, Lutjohann D, Jessen F, Wullner U, Harbrecht U et al (2004) Polymorphisms in glutathione S-transferase omega-1 and AD, vascular dementia, and stroke. Neurology 63:2255–2260

    PubMed  CAS  Google Scholar 

  49. Nishimura M, Sakamoto T, Kaji R, Kawakami H (2004) Influence of polymorphisms in the genes for cytokines and glutathione S-transferase omega on sporadic Alzheimer’s disease. Neurosci Lett 368:140–143

    Article  PubMed  CAS  Google Scholar 

  50. Ozturk A, Desai PP, Minster RL, Dekosky ST, Kamboh MI (2005) Three SNPs in the GSTO1, GSTO2 and PRSS11 genes on chromosome 10 are not associated with age-at-onset of Alzheimer’s disease. Neurobiol Aging 26:1161–1165

    Article  PubMed  CAS  Google Scholar 

  51. Higuchi M, Iwata N, Saido TC (2005) Understanding molecular mechanisms of proteolysis in Alzheimer’s disease: progress toward therapeutic interventions. Biochim Biophys Acta 1751:60–67

    PubMed  CAS  Google Scholar 

  52. Higuchi M, Tomioka M, Takano J, Shirotani K, Iwata N, Masumoto H et al (2005) Distinct mechanistic roles of calpain and caspase activation in neurodegeneration as revealed in mice overexpressing their specific inhibitors. J Biol Chem 280:15229–15237

    Article  PubMed  CAS  Google Scholar 

  53. Fathi Z, Battaglino PM, Iben LG, Li H, Baker E, Zhang D et al (1998) Molecular characterization, pharmacological properties and chromosomal localization of the human GALR2 galanin receptor. Brain Res Mol Brain Res 58:156–169

    Article  PubMed  CAS  Google Scholar 

  54. Taguchi K, Yamagata HD, Zhong W, Kamino K, Akatsu H, Hata R et al (2005) Identification of hippocampus-related candidate genes for Alzheimer’s disease. Ann Neurol 57:585–588

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

Funding for this project was provided by the National Institutes on Aging, National Institutes of Health R37 AG15473, National Heart, Lung and Blood Institute HV48141, and the Canadian Institutes of Health Research. In addition, support was provided by the Charles S. Robertson Gift for Research on Alzheimer’s Disease from the Banbury fund. We also thank the members of Estudio Familiar de Influencia Genetica en Alzheimer, The Sociedad Dominicana de Geriatria y Gerontologia, The Sociedad Dominicana de Neurologia y Neurocirugia, The Sociedad Dominicana de Psiquiatria, and the Associacion Dominicana Alzheimer y Similares, and The Bioethics National Committee for Research in the Dominican Republic.

Author information

Authors and Affiliations

  1. The Taub Institute on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

    Joseph H. Lee, Sandra Barral, Rong Cheng, Vincent Santana, Jennifer Williamson, Rafael Lantigua, Yaakov Stern, Benjamin Tycko & Richard Mayeux

  2. Gertrude H. Sergievsky Center, Columbia University, 630 West 168th Street, New York, NY, 10032, USA

    Joseph H. Lee, Rong Cheng, Inara Chacon, Vincent Santana, Jennifer Williamson, Yaakov Stern & Richard Mayeux

  3. The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Yaakov Stern & Richard Mayeux

  4. The Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Yaakov Stern & Richard Mayeux

  5. The Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Rafael Lantigua

  6. The Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Benjamin Tycko

  7. The Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA

    Joseph H. Lee & Richard Mayeux

  8. The Universidad Tecnologica de Santiago, Santiago de los Caballeros, Dominican Republic

    Martin Medrano

  9. The Department of Internal Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico

    Ivonne Z. Jimenez-Velazquez

  10. Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, and Toronto Western Hospital Research Institute, Toronto, ON, Canada

    Ekaterina Rogaeva, Yosuke Wakutani, Toshitaka Kawarai & Peter St George-Hyslop

Authors
  1. Joseph H. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra Barral
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Inara Chacon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vincent Santana
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jennifer Williamson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rafael Lantigua
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martin Medrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ivonne Z. Jimenez-Velazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yaakov Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Benjamin Tycko
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ekaterina Rogaeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yosuke Wakutani
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Toshitaka Kawarai
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Peter St George-Hyslop
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Richard Mayeux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard Mayeux.

Additional information

Joseph H. Lee, Sandra Barral, Rong Cheng, and Inara Chacon contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material. Supplemental Figures. The results from two-point linkage analysis are presented for each chromosome separately. Solid line represents LOD scores from the APOE-ɛ4-positive conditional analysis, while the dotted line represents LOD scores from the APOE unadjusted analysis

Fig. S1a

Probable&PossibleAD. C1-C10 (GIF 63 KB)

10048_2007_103_Fig1_ESM.tif

Fig. S1b

Probable&Possible. C11-C22 (GIF 62 KB)

10048_2007_103_Fig2_ESM.tif

Fig. S2a

Probable. C1-C10 (GIF 66 KB)

10048_2007_103_Fig3_ESM.tif

Fig. S2b

Probable. C11-C22 (GIF 61 KB)

10048_2007_103_Fig4_ESM.tif

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, J.H., Barral, S., Cheng, R. et al. Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease. Neurogenetics 9, 51–60 (2008). https://doi.org/10.1007/s10048-007-0103-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-007-0103-3

Keywords

Search

Navigation