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.

  • Original Research Article
  • Published:

Value of CSF β-amyloid1–42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Molecular Psychiatry volume 9, pages 705–710 (2004)Cite this article

Abstract

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) β-amyloid1–42 (Aβ1–42) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Aβ1–42 and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Aβ1–42 and CSF tau. The levels of CSF tau were increased, whereas levels of Aβ1–42 were decreased in MCI subjects. Aβ1–42 predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Aβ1–42, but not other predictor variables (tau protein, gender, age, apolipoprotein E ɛ4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Aβ1–42 may be useful biomarkers in the early identification of AD in MCI subjects.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

Similar content being viewed by others

References

  1. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E . Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56: 303–308.

    Article  CAS  Google Scholar 

  2. Morris JC, Price AL . Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer's disease. J Mol Neurosci 2001; 17: 101–118.

    Article  CAS  Google Scholar 

  3. Galasko D, Clark C, Chang L, Miller B, Green RC, Rotter R et al. Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer's disease. Neurology 1997; 48: 632–635.

    Article  CAS  Google Scholar 

  4. Riemenschneider M, Buch K, Schmolke M, Kurz A, Guder WG . Cerebrospinal protein tau is elevated in early Alzheimer's disease. Neurosci Lett 1996; 212: 209–211.

    Article  CAS  Google Scholar 

  5. Motter R, Vigo-Pelfrey C, Kholodenko D, Barbour R, Johnson-Wood K, Galasko D et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol 1995; 38: 643–648.

    Article  CAS  Google Scholar 

  6. Galasko D, Chang L, Motter R, Clark CM, Kaye J, Knopman D et al. High cerebrospinal fluid tau and low amyloid-beta-42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998; 55: 937–945.

    Article  CAS  Google Scholar 

  7. Andreasen N, Hesse C, Davidsson P, Minthon L, Wallin A, Winblad B et al. Cerebrospinal fluid beta-amyloid(1–42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol 1999; 56: 673–680.

    Article  CAS  Google Scholar 

  8. Arai H, Nakagawa T, Kosaka Y, Higuchi M, Matsui T, Okamura N et al. Elevated cerebrospinal fluid tau protein level as a predictor of dementia in memory-impaired individuals. Alzheim Res 1997; 3: 211–213.

    Google Scholar 

  9. Andreasen N, Minthon L, Vanmechelen E, Vanderstichele H, Davidsson P, Winblad B et al. Cerebrospinal fluid tau and A-beta42 as predictors of development of Alzheimer's disease in patients with mild cognitive impairment. Neurosci Lett 1999; 273: 5–8.

    Article  CAS  Google Scholar 

  10. Riemenschneider M, Lautenschlager N, Wagenpfeil S, Diehl J, Drzezga A, Kurz A . Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment. Arch Neurol 2002; 59: 1729–1734.

    Article  CAS  Google Scholar 

  11. Sjögren M, Vanderstichele H, Agren H, Zachrisson O, Edsbagge M, Wikkelso C et al. Tau and Abeta42 in cerebrospinal fluid from healthy adults 21–93 years of age: establishment of reference values. Clin Chem 2001; 47: 1776–1781.

    PubMed  Google Scholar 

  12. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . 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 1984; 34: 939–944.

    Article  CAS  Google Scholar 

  13. Rosen WG, Mohs RC, Davis KL . A new rating scale for Alzheimer's disease. Am J Psychiatry 1984; 141: 1356–1364.

    Article  CAS  Google Scholar 

  14. Morris JC . The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993; 43: 2412–2414.

    Article  CAS  Google Scholar 

  15. Cox DR . Regression models and live-table. J R Statist Soc 1972; 34: 187–202.

    Google Scholar 

  16. Blennow K, Hampel H . Cerebrospinal fluid markers for incipient Alzheimer's disease. Lancet Neurol 2003; 2: 605–613.

    Article  CAS  Google Scholar 

  17. Hampel H, Goernitz A, Buerger K . Advances in the development of biomarkes for Alzheimer's disease. From CSF total tau and Aβ1–42 proteins to phosphorylated tau protein. Brain Res Bull 2003; 61: 243–253.

    Article  CAS  Google Scholar 

  18. Blennow K, Vanmechelen E, Hampel H . CSF total tau, Aβ42 and phosphorylated tau protein as biomarkers for Alzheimer's disease. Mol Neurobiol 2002; 24: 87–97.

    Article  Google Scholar 

  19. Hulstaert F, Blennow K, Ivanoiu A, Schoonderwaldt HC, Riemenschneider M, De Deyn PP et al. Improved discrimination of AD patients using beta-amyloid (1–42) and tau levels in CSF. Neurology 1999; 52: 1555–1562.

    Article  CAS  Google Scholar 

  20. Maruyama M, Arai H, Sugita M, Tanji H, Higuchi M, Okamura N et al. Cerebrospinal fluid amyloid beta(1–42) levels in the mild cognitive impairment stage of Alzheimer's disease. Exp Neurol 2001; 172: 433–436.

    Article  CAS  Google Scholar 

  21. Jensen M, Basun H, Lannfeldt L . Increased cerebrospinal fluid tau in patients with Alzheimer's disease. Neurosci Lett 1995; 186: 189–191.

    Article  CAS  Google Scholar 

  22. Flicker C, Ferris SH, Reisberg B . A longitudinal study of cognitive function in elderly persons with subjective memory complaints. J Am Geriatr Soc 1993; 41: 1029–1032.

    Article  CAS  Google Scholar 

  23. Clarnette R, Almeida O, Forstl H, Paton A, Martins RN . Clinical characteristics of individuals with subjective memory loss in Western Australia: results from a cross-sectional survey. Int J Geriatr Psychiatry 2001; 16: 168–174.

    Article  CAS  Google Scholar 

  24. Schofield PW, Marder K, Dooneief G, Jacobs DM, Sano M, Stern Y . Association of subjective memory complaints with subsequent cognitive decline in community-dwelling elderly individuals with baseline cognitive impairment. Am J Psychiatry 1997; 154: 609–615.

    Article  CAS  Google Scholar 

  25. Jensen M, Schroeder J, Blomberg M, Engvall B, Pantel J, Ida N et al. Cerebrospinal fluid A beta42 is increased early in sporadic Alzheimer's disease and declines with disease progression. Ann Neurol 1999; 45: 504–511.

    Article  CAS  Google Scholar 

  26. Kanai M, Matsubara E, Isoe K, Urakami K, Nakashima K, Arai H et al. Longitudinal study of cerebrospinal fluid levels of tau, A-beta1-40, and A-beta1-42(43) in Alzheimer's disease: a study in Japan. Ann Neurol 1998; 44: 17–26.

    Article  CAS  Google Scholar 

  27. Riemenschneider M, Schmolke M, Lautenschlager N, Guder WG, Vanderstichele H, Vanmechelen E et al. Cerebrospinal beta-amyloid (1–42) in early Alzheimer's disease: association with apolipoprotein E genotype and cognitive decline. Neurosci Lett 2000; 284: 85–88.

    Article  CAS  Google Scholar 

  28. Shoji M, Matsubara E, Kanai M, Watanabe M, Nakamura T, Tomidokoro Y et al. Combination assay of CSF tau, A-beta1-40, A-beta1-42(43) as a biochemical marker of Alzheimer's disease. J Neurol Sci 1998; 158: 134–140.

    Article  CAS  Google Scholar 

  29. Tamaoka A, Sawamura N, Fukushima T, Shoji S, Matsubara E, Shoji M et al. Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease. J Neurol Sci 1997; 148: 41–45.

    Article  CAS  Google Scholar 

  30. Sjögren M, Minthon L, Davidsson P, Granerus AK, Clarberg A, Vanderstichele H et al. CSF levels of tau, beta-amyloid(1–42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging. J Neural Transm 2000; 107: 563–579.

    Article  Google Scholar 

  31. Buerger K, Teipel SJ, Zinkowski R, Blennow K, Arai H, Engel R et al. CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology 2002; 59: 627–629.

    Article  CAS  Google Scholar 

  32. Arai H, Ishiguro K, Ohno H, Moriyama M, Itoh N, Okamura N et al. CSF phosphorylated tau protein and mild cognitive impairment: a prospective study. Exp Neurol 2000; 166: 201–203.

    Article  CAS  Google Scholar 

  33. Frank RA, Galasko D, Hampel H, Hardy J, De Leon M, Mehta PD et al. Biological markers for therapeutic trials in Alzheimer's disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease. Neurobiol Aging 2003; 24: 521–536.

    Article  Google Scholar 

  34. Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, Andreasen N et al. Measurementof phosphorylated tau epitopes in the differential diagnosis of Alzheimer's disease - a comparative CSF study. Arch Gen Psychiatry, (in press).

Download references

Acknowledgements

This work was supported by grants of the Volkswagen-Foundation, Hannover, Germany (HH), the Hirnliga, Nürmbrecht, Germany (HH and KB), the Medical School of the Ludwig-Maximilian University, Munich, Germany (Foerderprogramm fuer Forschung und Lehre, KB, SJT, and HH). We thank Felician Jancu, Bea Riemenschneider, and Christine Sänger for clinical support and Thomas Nolde and Michael Ewers, PhD, for technical assistance. We thank Jens Prüssner, PhD, and Arun Bokde, PhD, for critical discussion of the manuscript.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Dementia Research Section and Memory Clinic, Ludwig-Maximilian University, Nussbaumstrasse, Munich, Germany

    H Hampel, S J Teipel, T Fuchsberger, H-J Möller & K Buerger

  2. Division of Geriatric Medicine, Karolinska Institutet, Neurotec, Huddinge University Hospital, Stockholm, Sweden

    N Andreasen

  3. Department of Psychiatry, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage, Erlangen, Germany

    J Wiltfang

  4. Department of Neurology, Georg-August University, von-Siebold-Strasse, Göttingen, Germany

    M Otto

  5. Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, West Santa Fe Drive, Sun City, AZ, USA

    Y Shen

  6. Department of Neurology, Rheinische Friedrich-Wilhelms-University Bonn, Sigmund-Freudstr., Bonn, Germany

    R Dodel

  7. Department of Neurology, Indiana University Medical School, Indianapolis, IN, USA

    Y Du & M Farlow

  8. Department of Clinical Neuroscience, Unit of Neurochemistry, University of Göteborg, Sahlgren's University Hospital, Mölndal, Sweden

    K Blennow

Authors
  1. H Hampel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S J Teipel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Fuchsberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Andreasen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Wiltfang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R Dodel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Farlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H-J Möller
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. K Blennow
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K Buerger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Buerger.

Additional information

Previous presentation: Parts of this work have been presented in abstract form at scientific meetings.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hampel, H., Teipel, S., Fuchsberger, T. et al. Value of CSF β-amyloid1–42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment. Mol Psychiatry 9, 705–710 (2004). https://doi.org/10.1038/sj.mp.4001473

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001473

Keywords

This article is cited by

Search

Advanced search

Quick links