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 Article
  • Published:

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study

Molecular Psychiatry volume 15, pages 138–145 (2010)Cite this article

Abstract

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins α and β (sAPPα and sAPPβ) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination⩾20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloidβ peptides, Tau and phospho-Tau. sAPPα and sAPPβ were measured with multiplexing method based on electrochemiluminescence. sAPPα and sAPPβ CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPPα and sAPPβ CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPPα and sAPPβ highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPPα: cutoff, 117.4 ng ml−1, sensitivity, 68%, specificity, 85%, P<0.001; sAPPβ: cutoff, 181.8 ng ml−1, sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPPα and sAPPβ might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

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
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Mayeux R . Evaluation and use of diagnostic tests in Alzheimer's disease. Neurobiol Aging 1998; 19: 139–143.

    Article  CAS  Google Scholar 

  2. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J . Therapeutic approaches to Alzheimer's disease. Brain 2006; 129: 2840–2855.

    Article  Google Scholar 

  3. Hull M, Berger M, Heneka M . Disease-modifying therapies in Alzheimer's disease: how far have we come? Drugs 2006; 66: 2075–2093.

    Article  Google Scholar 

  4. The Working Group on: ‘Molecular and Biochemical Markers of Alzheimer's Disease’. Consensus report of the Working Group on: ‘Molecular and Biochemical Markers of Alzheimer's Disease’. The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. Neurobiol Aging 1998; 19: 109–116.

    Article  Google Scholar 

  5. Wiltfang J, Lewczuk P, Riederer P, Grünblatt E, Hock C, Scheltens P et al. Consensus paper of the WFSBP task force on biological markers of dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia. World J Biol Psychiatry 2005; 6: 69–84.

    Article  CAS  Google Scholar 

  6. Lewczuk P, Wiltfang J . Neurochemical dementia diagnostics: state of the art and research perspectives. Proteomics 2008; 8: 1292–1301.

    Article  CAS  Google Scholar 

  7. Andreasen N, Minthon L, Davidsson P, Vanmechelen E, Vanderstichele H, Winblad B et al. Evaluation of CSF-tau and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001; 58: 373–379.

    Article  CAS  Google Scholar 

  8. Blennow K, Wallin A, Hager O . Low frequency of post-lumbar puncture headache in demented patients. Acta Neurol Scand 1993; 88: 221–223.

    Article  CAS  Google Scholar 

  9. Olsson A, Vanderstichele H, Andreasen N, De Meyer G, Wallin A, Holmberg B et al. Simultaneous measurement of beta-amyloid(1–42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 2005; 51: 336–345.

    Article  CAS  Google Scholar 

  10. Lewczuk P, Kornhuber J, Vanderstichele H, Vanmechelen E, Esselmann H, Bibl M et al. Multiplexed quantification of dementia biomarkers in the CSF of patients with early dementias and MCI: a multicenter study. Neurobiol Aging 2008; 29: 812–818.

    Article  CAS  Google Scholar 

  11. 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 Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939–944.

    Article  CAS  Google Scholar 

  12. Thalmann B, Monsch AU, Bernasconi F, Berres M, Schneitter M, Ermini-Fuenfschilling D et al. Die CERAD Neuropsychologische Testbatterie—Ein gemeinsames minimales Instrumentarium zur Demenzabklärung. Memory Clinic, Geriatrische Universitätsklinik Basel: Basel, 1998.

    Google Scholar 

  13. Härting C, Markowitsch HJ, Neufeld H, Calabrese P, Deisinger K . Deutsche Adaptation der revidierten Fassung der Wechsler-Memory Scale (WMS-R). Verlag Hans Huber: Bern, Göttingen, 2000.

    Google Scholar 

  14. Reitan RM . Trail Making Test (TMT). Hogrefe Verlag: Bern, Göttingen, 1979.

    Google Scholar 

  15. Shulman KI, Shedletsky R, Silver IL . Challenge of time: clock-drawing and cognitive function in the elderly. Int J Ger Psychiatr 1986; 1: 135–140.

    Article  Google Scholar 

  16. Hindmarch I, Lehfeld H, de Jongh P, Erzigkeit H . The bayer activities of daily living scale (B-ADL). Dement Geriatr Cogn Disord 1998; 9 (Suppl 2): 20–26.

    Article  Google Scholar 

  17. Jorm AF . A short form of the informant questionnaire on cognitive decline in the elderly (IQCODE): development and cross-validation. Psychol Med 1994; 24: 145–153.

    Article  CAS  Google Scholar 

  18. Morris JC . The clinical dementia rating (CDR): current version and scoring rules. Neurology 1993; 43: 2412–2414.

    Article  CAS  Google Scholar 

  19. Folstein MF, Folstein SE, McHugh PR . Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.

    Article  CAS  Google Scholar 

  20. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV et al. Current concepts in mild cognitive impairment. Arch Neurol 2001; 58: 1985–1992.

    Article  CAS  Google Scholar 

  21. Lewczuk P, Esselmann H, Otto M, Maler JM, Henkel AW, Henkel MK et al. Neurochemical diagnosis of Alzheimer's dementia by CSF Aβ42, Aβ42/Aβ40 ratio and total tau. Neurobiol Aging 2004; 25: 273–281.

    Article  CAS  Google Scholar 

  22. Lewczuk P, Kornhuber J, Wiltfang J . The German competence net dementias: standard operating procedures for the neurochemical dementia diagnostics. J Neural Transm 2006; 113: 1075–1080.

    Article  CAS  Google Scholar 

  23. Lewczuk P, Esselmann H, Bibl M, Beck G, Maler JM, Otto M et al. Tau protein phosphorylated at threonine 181 in CSF as a neurochemical biomarker in Alzheimer's disease: original data and review of the literature. J Mol Neurosci 2004; 23: 115–122.

    Article  CAS  Google Scholar 

  24. Ehehalt R, Michel B, De Pietri Tonelli D, Zacchetti D, Simons K, Keller P . Splice variants of the beta-site APP-cleaving enzyme BACE1 in human brain and pancreas. Biochem Biophys Res Commun 2002; 293: 30–37.

    Article  CAS  Google Scholar 

  25. Tampellini D, Magrane J, Takahashi RH, Li F, Lin MT, Almeida CG et al. Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations. J Biol Chem 2007; 282: 18895–18906.

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  27. Lewczuk P, Kornhuber J, Vanderstichele H, Vanmechelen E, Esselmann H, Bibl M et al. Multiplexed quantification of dementia biomarkers in the CSF of patients with early dementias and MCI: a multicenter study. Neurobiol Aging 2008; 29: 812–818.

    Article  CAS  Google Scholar 

  28. Lewczuk P, Beck G, Ganslandt O, Esselmann H, Deisenhammer F, Regeniter A et al. International quality control survey of neurochemical dementia diagnostics. Neurosci Lett 2006; 409: 1–4.

    Article  CAS  Google Scholar 

  29. Lewczuk P, Esselmann H, Bibl M, Paul S, Svitek J, Miertschischk J et al. Electrophoretic separation of amyloid beta peptides in plasma. Electrophoresis 2004; 25: 3336–3343.

    Article  CAS  Google Scholar 

  30. Bibl M, Esselmann H, Otto M, Lewczuk P, Cepek L, Rüther E et al. Cerebrospinal fluid amyloid β peptide patterns in Alzheimer's disease patients and nondemented controls depend on sample pretreatment: indication of carrier-mediated epitope masking of amyloid beta peptides. Electrophoresis 2004; 25: 2912–2918.

    Article  CAS  Google Scholar 

  31. Engelborghs S, De Vreese K, Van de Casteele T, Vanderstichele H, Van Everbroeck B, Cras P et al. Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia. Neurobiol Aging 2008; 29: 1143–1159.

    Article  Google Scholar 

  32. Zetterberg H, Wahlund LO, Blennow K . Cerebrospinal fluid markers for prediction of Alzheimer's disease. Neurosci Lett 2003; 352: 67–69.

    Article  CAS  Google Scholar 

  33. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L . Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006; 5: 228–234.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the following grants from the German Federal Ministry of Education and Research (BMBF): Kompetenznetz Demenzen (01 GI 0420), HBPP-NGFN2 (01 GR 0447), and the Forschungsnetz der Früh- und Differenzialdiagnose der Creutzfeldt-Jakob-Krankheit und der neuen Variante der CJK (01 GI 0301), and by the EU grants cNEUPRO (contract no. LSHM-CT-2007-037950), and neuroTAS (contract no. LSHB-CT-2006-037953). We appreciate aliquots of 6E10 and ANGU antibodies provided by Dr R Umek (Meso-Scale Discovery) for western blot experiments.

Author information

Author notes

  1. J Wiltfang

    Present address: 16Current address: Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Virchowstr. 174, D-45147 Essen, Germany,

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany

    P Lewczuk, H Kamrowski-Kruck, H-W Klafki, U Reulbach, H Esselmann, J M Maler, J Kornhuber & J Wiltfang

  2. Department of Psychiatry and Psychotherapy, Charité—Universitätsmedizin Berlin, Berlin, Germany

    O Peters & I Heuser

  3. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

    F Jessen, J Popp & H Kölsch

  4. Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, Munich, Germany

    K Bürger & H Hampel

  5. Discipline of Psychiatry, School of Medicine & Trinity College Institute of Neuroscience (TCIN), Trinity College, University of Dublin, The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Dublin, Ireland

    H Hampel

  6. Division of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

    L Frölich

  7. Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany

    S Wolf, B Prinz & M Bibl

  8. Department of Psychiatry and Psychotherapy, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    H Jahn

  9. Department of Psychiatry and Psychotherapy, University of Düsseldorf, Düsseldorf, Germany

    Ch Luckhaus

  10. Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany

    R Perneczky

  11. Centre for Geriatric Medicine and Gerontology, Section of Gerontopsychiatry and Neuropsychology, University of Freiburg, Freiburg, Germany

    M Hüll

  12. Department of Psychiatry and Psychotherapy, University of Heidelberg, Heidelberg, Germany

    J Schröder

  13. Department of Psychiatry and Psychotherapy, University of Saarland, Homburg, Germany

    H Kessler

  14. Department of Psychiatry, Psychosomatic and Psychotherapy, University of Frankfurt, Frankfurt, Germany

    J Pantel

  15. Department of Psychiatry, University of Leipzig, Leipzig, Germany

    H-J Gertz

Authors
  1. P Lewczuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Kamrowski-Kruck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Heuser
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F Jessen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Popp
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Bürger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Hampel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Frölich
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B Prinz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. H Jahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ch Luckhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R Perneczky
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M Hüll
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J Schröder
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. H Kessler
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. J Pantel
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. H-J Gertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. H-W Klafki
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. H Kölsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. U Reulbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. H Esselmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. J M Maler
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. M Bibl
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. J Kornhuber
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. J Wiltfang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Wiltfang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lewczuk, P., Kamrowski-Kruck, H., Peters, O. et al. Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study. Mol Psychiatry 15, 138–145 (2010). https://doi.org/10.1038/mp.2008.84

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.84

Keywords

This article is cited by

Search

Advanced search

Quick links