Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Alpha-2 macroglobulin is genetically associated with Alzheimer disease

Nature Genetics volume 19, pages 357–360 (1998)Cite this article

Abstract

Alpha-2-macroglobulin (α-2M; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of Aß, the major component of ß-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2 ) confers increased risk for AD (Mantel-Haenzel odds ratio = 3.56, P = 0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P = 0.00009). These values were comparable to those obtained for the APOE-ε4 allele in the same sample, but in contrast to APOE-ε4, A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the α-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid ß-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Map of chromosome 12 markers.

References

  1. Blacker, D. & Tanzi, R.E. The genetics of Alzheimer's disease: current status and future prospects. Arch. Neurol. 55, 294–296 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Strittmatter, W.J. et al. Apolipoprotein E: High avidity binding to ß-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977– 1981 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Blacker, D. et al. APOE-4 and age-at-onset of Alzheimer's disease: the NIMH Genetics Initiative . Neurology 48, 139–147 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Farrer, L.A. et al. 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. J.A.M.A. 278, 1349–1356 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Kang, D.E. et al. 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 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Kounnas, M. et al. LDL-receptor-related protein, a multifunctional ApoE receptor, binds secreted ß-amyloid precursor protein and mediates its degradation. Cell 82, 331–340 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  7. Borth, W. Alpha-2-macroglobulin, a multi-functional binding protein with targeting characteristics. F.A.S.E.B. J. 6, 3345–3353 (1992).

    CAS  Google Scholar 

  8. Strickland, D.K. et al. Sequence identity between the alpha-2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J. Biol. Chem. 265, 17401– 17404 (1990).

    CAS  PubMed  Google Scholar 

  9. Lopes, M.B., Bogaev, C.A., Gonias, S.L. & Vandenberg, S.R. Expression of alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein is increased in reactive and neoplastic glial cells. F.E.B.S. Lett. 338, 301–305 ( 1993).

    Article  Google Scholar 

  10. Rebeck, W.G., Harr, S.D., Strickland, D.K. & Hyman, B.T. Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the α2-macroglobulin receptor/low-density-lipoprotein receptor-related protein. Ann. Neurol. 37, 211– 217 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Du, Y. et al. Alpha-2-macroglobulin as a beta-amyloid peptide-binding plasma protease. J. Neurochem. 69, 299–305 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  12. Hughes, S.R. et al. Alpha-2-macroglobulin associates with ß-amyloid peptide and prevents fibril formation. Proc. Natl Acad. Sci. USA 95, 3275–3280 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Du, Y. et al. Alpha-2-macroglobulin attenuates beta-amyloid peptide 1-40 fibril formation and associated neurotoxicity of cultured fetal rat cortical neurons. J. Neurochem. 70, 1182–1188 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Qiu, W.Q. et al. Degradation of amyloid beta protein by a serine proteinase alpha-2-macroglobulin complex. J. Biol. Chem. 271, 8443– 8451 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Narita, M., Holtzman, D.M., Schwartz, A.L. & Bu, G. Alpha-2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J. Neurochem. 69, 1904–1911 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  16. Pericak-Vance, M.A. et al. Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. J.A.M.A. 278, 1237–1241 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Matthijs, G. & Marynen, P. A deletion polymorphism in the human alpha-2-macroglobulin (A2M) gene. Nuceic Acids Res. 19, 5102 (1991).

    Article  CAS  Google Scholar 

  18. Spielman, R.S. & Ewens, W.J. A sibship test for linkage in the presence of association: The Sib Transmission/Disequilibrium. Am. J. Hum. Genet. 62, 450–458 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Krauter, K. et al. A second-generation YAC contig map of human chromosome 12. Nature 377, 321–333 ( 1995).

    CAS  PubMed  Google Scholar 

  20. Wu, W.S. et al. Genetic studies on chromosome 12 in late onset Alzheimer's disease. J.A.M.A. in press (1998).

  21. Meyer, M.R. et al. APOE polymorphism predicts when--not whether--individuals are predisposed to develop Alzheimer's disease. Nature Genet. 19, 321–322 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Bullido, M.J. et al. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia. Nature Genet. 18, 69– 71 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Lambert, J-C . et al. A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease. Hum. Mol. Genet. 7, 533–540 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Lambert, J-C . et al. Distortion of allelic expression of apolipoprotein E in Alzheimer's disease . Hum. Mol. Genet. 6, 2151– 2154 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Bales, K.R. et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition . Nature Genet. 17, 263– 264 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, Z. et al. Inhibition of alpha-2-macroglobulin/proteinase-mediated degradation of amyloid beta peptide by apolipoprotein E and alpha-1-antichymotrypsin. Int. J. Exp. Clin. Invest. 3, 156– 161 (1996).

    CAS  Google Scholar 

  27. Hollenbach, E., Ackermann, S., Hyman, B.T. & Rebeck, G.W. Confirmation of an association between a polymorphism in exon 3 of LRP and Alzheimer's disease. Neurology, in press.

  28. Blacker, D. et al. Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease . Arch. Neurol. 51, 1198– 1204 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. McKhann, G. et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34, 939–944 (1984).

    Article  CAS  PubMed  Google Scholar 

  30. Farrer, L.A. et al. Transmission and age-at-onset patterns in familial Alzheimer's disease: evidence for heterogeneity. Neurology 40, 395– 403 (1990).

    Article  CAS  PubMed  Google Scholar 

  31. Corder, E.H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genet. 7, 180– 184 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Terwilliger, J.D. & Ott, J. Handbook of Human Genetic Linkage. (Johns Hopkins University Press, Baltimore, 1994).

    Google Scholar 

  33. Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank E. Wijsman, K. Lunetta, N.Cox, D. Neuberg and P. VanEerdewegh for advice regarding statistical genetics; M. Hyde for assistance with data analysis; and S. Moldin and staff at NIMH and at all three sites for assistance with all aspects of the project. The authors are also extremely grateful to the families whose participation made this work possible. This work was supported by grants from the National Institute of Mental Health (NIMH) to M.S.A. (U01 MH46281, U01 MH51066), D.B. (K21 MH01118), N.M.L. (T32-MH17119), S.S.B. (U01 MH46290, U01 MH52042) and R.C.P.G. (U01 MH46373, U01 MH51024). The NIMH Alzheimer Disease Genetics Initiative is a multi-site study performed by three independent research teams in collaboration with extramural staff from the NIMH. The principal investigators and co-investigators from the three sites are: MGH, M.S.A., R.E.T. and D.B.; JHU, S.S.B., G. A. Chase and M. F. Folstein; UAB, R.C.P.G. and L. E. Harrell.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School,

    Deborah Blacker & Marilyn S. Albert

  2. Genetics and Aging Unit, Massachusetts General Hospital and Harvard Medical School,

    Linda Rodes & Rudolph E. Tanzi

  3. Department of Neurology, Massachusetts General Hospital and Harvard Medical School,

    Linda Rodes, Marilyn S. Albert, Bradley T. Hyman & Rudolph E. Tanzi

  4. Department of Epidemiology, Harvard School of Public Health,

    Deborah Blacker & Marsha A. Wilcox

  5. Department of Biostatistics, Harvard School of Public Health,

    Nan M. Laird & Steven M. Horvath

  6. Department of Epidemiology, University of Alabama at Birmingham,

    Rodney C.P. Go, Rodney Perry & Bracie Watson Jr.

  7. Department of Psychiatry, Johns Hopkins University Medical Institutions,

    Susan S. Bassett & Melvin G. McInnis

Authors
  1. Deborah Blacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marsha A. Wilcox
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan M. Laird
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linda Rodes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven M. Horvath
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rodney C.P. Go
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rodney Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bracie Watson Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Susan S. Bassett
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Melvin G. McInnis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marilyn S. Albert
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bradley T. Hyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Rudolph E. Tanzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rudolph E. Tanzi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Blacker, D., Wilcox, M., Laird, N. et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease . Nat Genet 19, 357–360 (1998). https://doi.org/10.1038/1243

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/1243

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing