Journal Mobile Options
Table of Contents
Vol. 15, No. 3, 2003
Issue release date: February 2003
Dement Geriatr Cogn Disord 2003;15:169–176

Cerebrospinal Fluid Beta-Amyloid 42 Is Reduced before the Onset of Sporadic Dementia: A Population-Based Study in 85-Year-Olds

Skoog I. · Davidsson P. · Aevarsson Ó. · Vanderstichele H. · Vanmechelen E. · Blennow K.
aInstitute of Clinical Neuroscience, Unit of Neuropsychiatric Epidemiology, University of Göteborg, Sahlgrenska University Hospital, Göteborg, bInstitute of Clinical Neuroscience, Department of Experimental Neuroscience, Unit of Neurochemistry, University of Göteborg, Sahlgrenska University Hospital, Mölndal, and cThe Medical Research Council, Sweden; dInnogenetics, Ghent, Belgium

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Deposition of β-amyloid (Aβ) is an early pathogenic event in Alzheimer’s disease (AD). We measured Aβ42 and Aβ40 in cerebrospinal fluid (CSF) in a population-based sample of 85-year-olds, 27 demented and 35 non-demented. During the following 3 years, 7 of the 35 non-demented individuals had developed dementia, while 28 remained non-demented. Reduced CSF levels of both Aβ42 (p = 0.001) and Aβ40 (p = 0.0001) were found in patients with manifest AD and vascular dementia at the age of 85. Non-demented individuals who developed dementia during follow-up had lower levels of CSF- Aβ42 (p = 0.003), but not CSF-Aβ40 (p = 0.96), than those who remained non-demented. The odds ratio for development of dementia was 8.2 (p = 0.027) for individuals in the lower 50th percentile of CSF-Aβ42, while none of those in the highest 33rd percentile of CSF-Aβ42 developed dementia during follow-up. There were no significant differences between carriers and non-carriers of the apolipoprotein E ε4 allele regarding CSF-Aβ42or CSF-Aβ40.Our study suggests that low CSF-Aβ42 is found also in an unselected population-based sample of old demented patients and provides the first evidence of a disturbance in the metabolism of Aβ, specifically involving Aβ42, before the onset of clinical symptoms in AD.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. 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.
  2. Lendon CL, Ashall F, Goate AM: Exploring the etiology of Alzheimer disease using molecular genetics. JAMA 1997;227:825–831.
  3. Yankner BA: Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 1996;16:921–932.
  4. Selkoe DJ: The cell biology of β-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 1998;8:447–453.

    External Resources

  5. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ: Sequence of deposition of heterogeneous amyloid beta-peptides and APOE in Down syndrome: Implications for initial events in amyloid plaque formation. Neurobiol Dis 1996;3:16–32.
  6. Jarret JT, Berger EP, Lansbury PT: The C-terminus of the beta protein is critical in amyloidogenesis. Ann NY Acad Sci 1993;695:144–148.
  7. Tamaoka A, Kondo T, Odaka A, Sahara N, Sawamura N, Ozawa K, Suzuki N, Shoji S, Mori H: Biochemical evidence for the long-tail form (Aβ 1–42/43) of amyloid β protein as a seed molecule in cerebral deposits of Alzheimer’s disease. Biochem Biophys Res Commun 1994;205:834–842.
  8. Hilbich C, Monning U, Grund C, Masters C, Beyreuther K: Amyloid-like properties of peptides flanking the epitope of amyloid precursor protein-specific monoclonal antibody 22C11. J Biol Chem 1993;268:26571–26577.
  9. Burdick D, Soreghan B, Kwon M, Kosmoski J, Knauer M, Henschen A, Yates J, Cotman C, Glabe C: Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. J Biol Chem 1992;267:17082–17086.
  10. Jarrett JT, Lansbury PT Jr: Seeding ‘one-dimensional crystallization’ of amyloid: A pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 1993;73:1055–1058.
  11. Blennow K, Skoog I: Genetic testing for Alzheimer’s disease: How close is reality? Curr Opin Psychiatry 1999;12:487–493.

    External Resources

  12. Regland B, Gottfries CG: The role of amyloid β-protein in Alzheimer’s disease. Lancet 1992;340:467–469.
  13. Davies P: Neuronal abnormalities, not amyloid, are the cause of dementia in Alzheimer disease; in Terry RD, Katzman R, Bick KL (eds): Alzheimer Disease. New York, Raven Press, 1994, pp 327–333.
  14. Tomlinson BE, Henderson G: Some quantitative cerebral findings in normal and demented old people; in Terry RD, Gershon S (eds): Neurobiology of Aging. New York, Raven Press, 1976, pp 183–204.
  15. Mann DMA, Yates PO, Marcyniuk B: Alzheimer’s presenile dementia, senile dementia of Alzheimer type and Down’s syndrome in middle age form an age related continuum of pathological changes. Neuropathol Appl Neurobiol 1984;10:185–207.
  16. Davies L, Wolska B, Hilbich C, Multhaup G, Martins R, Simms G, Beyreuther K, Masters CL: A4 amyloid protein deposition and the diagnosis of Alzheimer’s disease. Neurology 1988;38:1688–1693.
  17. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ: Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 1992;359:322–325.
  18. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert R, Selkoe D, Lieberburg I, Schenk D: Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 1992;359:325–327.
  19. Vigo-Pelfrey C, Lee D, Keim P, Lieberburg I, Schenk DB: Characterization of beta-amyloid peptide from human cerebrospinal fluid. J Neurochem 1993;61:19965–19968.
  20. Shoji M, Matsubara E, Kanai M, Watanabe M, Nakamura T, Tomidokoro Y, Shizuka M, Wakabayashi K, Igeta Y, Ikeda Y, Mizushima K, Amari M, Ishiguro K, Kawarabayashi T, Harigaya Y, Okamoto K, Hirai SJ: Combination assay of CSF tau, A beta 1–40 and A beta 1–42(43) as a biochemical marker of Alzheimer’s disease. J Neurol Sci 1998;158:134–140.
  21. Tamaoka A, Sawamura N, Fukushima T, Shoji S, Matsubara E, Shoji M, Hirai S, Furiya Y, Endoh R, Mori H: Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer’s disease. J Neurol Sci 1997;148:41–45.
  22. Vanderstichele H, Blennow K, D’Heuvaert N, Buyse MA, Wallin A, Andreasen N, Seubert P, Van de Voorde A, Vanmechelen E: Development of a specific diagnostic test for measurement of β-amyloid(1–42) [βA4(1–42)] in CSF; in Fischer A, Hanin I, Yoshida M (eds): Progress in Alzheimer’s and Parkinson’s diseases. New York, Plenum Press, 1998, pp 773–778.
  23. Hulstaert F, Blennow K, Ivanoiu A, Schoonderwaldt HC, Riemenschneider M, De Deyn PP, Bancher C, Cras P, Wiltfang J, Mehta PD, Iqbal K, Pottel H, Vanmechelen E, Vanderstichele H: Improved discrimination of AD patients using beta-amyloid(1–42) and tau levels in CSF. Neurology 1999;52:1555–1562.
  24. Andreasen N, Hesse C, Davidsson P, Minthon L, Wallin A, Winblad B, Vanderstichele H, Vanmechelen E, Blennow K: 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.
  25. Motter R, Vigo-Pelfrey C, Kholodenko D, Barbour R, Johnson-Wood K, Galasko D, Chang L, Miller B, Clark C, Green R, Olson D, Southwick P, Wolfert R, Munroe B, Lieberburg I, Seat P, Schenk D: Reduction of β-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 1995;38:643–648.
  26. Kanai M, Matsubara E, Isoe K, Urakami K, Nakashima K, Arai H, Sasaki H, Abe K, Iwatsubo T, Kosaka T, Watanabe M, Tomidokoro Y, Shizuka M, Mizushima K, Nakamura T, Igeta Y, Ikeda Y, Amari M, Kawarabayashi T, Ishiguro K, Harigaya Y, Wakabayashi K, Okamoto K, Hirai S, Shoji M: 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.
  27. Riemenschneider M, Schmolke M, Lautenschlager N, Guder WG, Vanderstichele H, Vanmechelen E, Kurz A: Cerebrospinal beta-amyloid(1–42) in early Alzheimer’s disease: Association with apolipoprotein E and cognitive decline. Neurosci Lett 2000;284:85–88.

    External Resources

  28. Andreasen N, Minthon L, Vanmechelen E, Vanderstichele H, Davidsson P, Winblad B, Blennow K: CSF-tau and CSF-Aβ42 as predictors of development of Alzheimer’s disease in patients with mild cognitive impairment. Neurosci Lett 1999;273:5–8.
  29. Skoog I, Nilsson L, Palmertz B, Andreasson L, Svanborg A: A population-based study of dementia in 85-year-olds. N Engl J Med 1993;328:153–158.
  30. Rinder L, Roupe S, Steen B, Svanborg A: Seventy-year-old people in Gothenburg: A population study in an industrialized Swedish city. I. General presentation of the study. Acta Med Scand 1975;198:397–407.
  31. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson L-A, Nilsson L, Persson G, Odén A, Svanborg A: A 15-year longitudinal study on blood pressure and dementia. Lancet 1996;347:1141–1145.
  32. Skoog I, Wallin A, Fredman P, Hesse C, Aevarsson O, Karlsson I, Gottfries CG, Blennow K: A population study on blood-brain barrier function in 85-year-olds. Relation to Alzheimer’s disease and vascular dementia. Neurology 1998;50:966–971.
  33. Aevarsson O, Skoog I: A population-based study on the incidence of dementia disorders between 85 and 88 years of age. J Am Geriatr Soc 1996;44:1455–1460.
  34. 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.
  35. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 3, revised. Washington, American Psychiatric Association, 1987.
  36. Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo J-M, Brun A, Hofman A, Moody DM, O’Brien MD, Yamaguchi T, Grafman J, Drayer BP, Bennett DA, Fisher M, Ogata J, Kokmen E, Bermejo F, Wolf PA, Gorelick PB, Bick KL, Pajeau AK, Bell MA, DeCarli C, Culebras A, Korczyn AD, Bogousslavsky J, Hartmann A, Scheinberg P: Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN international workshop. Neurology 1993;43:250–260.
  37. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL: A new clinical scale for the staging of dementia. Br J Psychiatry 1982;140:566–572.
  38. Skoog I, Hesse C, Aevarsson O, Landahl S, Wahlström J, Fredman P, Blennow K: A population study of Apo E genotype at the age of 85:Relation to dementia, cerebrovascular disease and mortality. J Neurol Neurosurg Psychiatry 1998;64:37–43.
  39. Cox DR, Hinkley DV: Theoretical Statistics. New York, Halsted Press, 1974.
  40. Iwatsubo T, Mann DMA, Odaka A, Suzuki N, Ihara Y: Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in Down syndrome. Ann Neurol 1995;37:294–299.
  41. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S: Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996;2:864–870.
  42. Gravina SA, Ho L, Eckman CB, Long KE, Otvos L Jr, Younkin LH, Suzuki N, Younkin SG: Amyloid beta protein (A beta) in Alzheimer’s disease brain: Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). J Biol Chem 1995;270:7013–7016.
  43. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ: Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 1997;3:67–72.
  44. Weller RO, Massey A, Newman TA, Hutchings M, Kuo Y-M, Roher AE: Cerebral amyloid angiopathy: Amyloid β accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol 1998;153:725–733.
  45. Lim A, Tsuang D, Kukull W, Nochlin D, Leverenz J, McCormick W, Bowen J, Teri L, Thompson J, Peskind ER, Raskind M, Larson EB: Clinico-neuropathological correlation of Alzheimer’s disease in a community-based case series. J Am Geriatr Soc 1999;47:564–569.
  46. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR: Brain infarction and the clinical expression of Alzheimer disease: The Nun Study. JAMA 1997;277:813–817.
  47. Sparks DL, Hunsaker JC III, Scheff SW, Kryscio RJ, Henson JL, Markesbery WR: Cortical senile plaques in coronary artery disease, aging and Alzheimer’s disease. Neurobiol Aging 1990;11:601–607.
  48. Skoog I: Guest editorial: Status of risk factors for vascular dementia. Neuroepidemiology 1998;17:2–9.
  49. Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinisto L, Halonen P, Kontula K: Apolipoprotein E, dementia, and cortical deposition of β-amyloid protein. N Engl J Med 1995;333:1242–1247.
  50. Galasko D, Chang L, Motter R, Clark CM, Kaye J, Knopman D, Thomas R, Kholodenko D, Schenk D, Lieberburg I, Miller B, Green R, Basherad R, Kertiles L, Boss MA, Seubert P: High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998;55:937–945.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50