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Plasma Aβ42/40 Ratio Detects Early Stages of Alzheimer’s Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study

  • V. Pérez-Grijalba
  • J. Romero
  • Pedro Pesini
  • L. Sarasa
  • I. Monleón
  • I. San-José
  • J. Arbizu
  • P. Martínez-Lage
  • J. Munuera
  • A. Ruiz
  • L. Tárraga
  • M. Boada
  • M. Sarasa
  • The AB255 Study Group
Original Research

Abstract

Background

Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer’s disease (AD) in large population screening strategies.

Objectives

This study evaluated the potential of plasma β-amyloid (Aβ) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years.

Design

Total plasma Aβ42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern.

Results

Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a highrisk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF).

Conclusions

TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.

Key words

β-amyloid (Aβ) Alzheimer’s disease plasma biomarker Aβ ratio 

Supplementary material

References

  1. 1.
    Lacosta AM, Insua D, Badi H, Pesini P, Sarasa M. Neurofibrillary Tangles of Abetax–40 in Alzheimer’s Disease Brains. J Alzheimers Dis 2017;58:661–667.CrossRefPubMedGoogle Scholar
  2. 2.
    Brookmeyer R, Johnson E, Ziegler–Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 2007 Jul;3:186–191.CrossRefPubMedGoogle Scholar
  3. 3.
    Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild–to–moderate Alzheimer’s disease. N Engl J Med 2014 Jan 23;370:311–321.CrossRefPubMedGoogle Scholar
  4. 4.
    Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild–to–moderate Alzheimer’s disease. N Engl J Med 2014 Jan 23;370:322–333.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sperling RA, Rentz DM, Johnson KA, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med 2014 Mar;%19;6:228fs13.Google Scholar
  6. 6.
    Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011 May;7:270–279.Google Scholar
  7. 7.
    Bohnen NI, Djang DS, Herholz K, Anzai Y, Minoshima S. Effectiveness and safety of 18F–FDG PET in the evaluation of dementia: a review of the recent literature. J Nucl Med 2012 Jan;53:59–71.Google Scholar
  8. 8.
    Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 2006 Mar;59:512–519.CrossRefPubMedGoogle Scholar
  9. 9.
    Weiner MW, Veitch DP, Aisen PS, et al. The Alzheimer’s Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement 2012 Feb;8:S1–68.Google Scholar
  10. 10.
    Rowe CC, Bourgeat P, Ellis KA, et al. Predicting Alzheimer disease with beta–amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing. Ann Neurol 2013 Dec;74:905–913.Google Scholar
  11. 11.
    Blennow K, Dubois B, Fagan AM, Lewczuk P, de Leon MJ, Hampel H. Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers Dement 2015 Jan;11:58–69.Google Scholar
  12. 12.
    Hansson O, Zetterberg H, Vanmechelen E, et al. Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer’s disease in patients with mild cognitive impairment. Neurobiol Aging 2010 Mar;31:357–367.Google Scholar
  13. 13.
    Lopez OL, Kuller LH, Mehta PD, et al. Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study. Neurology 2008 May 6;70:1664–1671.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lovheim H, Elgh F, Johansson A, et al. Plasma concentrations of free amyloidbeta cannot predict the development of Alzheimer’s disease. Alzheimers Dement 2016 Sep 28;10.Google Scholar
  15. 15.
    Cosentino SA, Stern Y, Sokolov E, et al. Plasma beta–Amyloid and Cognitive Decline. Arch Neurol 2010 Aug 9.Google Scholar
  16. 16.
    Mehta PD, Pirttila T, Patrick BA, Barshatzky M, Mehta SP. Amyloid beta protein 1–40 and 1–42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett 2001 May 18;304:102–106.CrossRefPubMedGoogle Scholar
  17. 17.
    Chouraki V, Beiser A, Younkin L, et al. Plasma amyloid–beta and risk of Alzheimer’s disease in the Framingham Heart Study. Alzheimers Dement 2015 Mar;11:249–257.Google Scholar
  18. 18.
    Graff–Radford NR, Crook JE, Lucas J, et al. Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 2007 Mar;64:354–362.Google Scholar
  19. 19.
    Lambert JC, Schraen–Maschke S, Richard F, et al. Association of plasma amyloid beta with risk of dementia: the prospective Three–City Study. Neurology 2009 Sep 15;73:847–853.CrossRefPubMedGoogle Scholar
  20. 20.
    Fandos N, Perez–Grijalba V, Pesini P, et al. Plasma amyloid beta 42/40 ratios as biomarkers for amyloid beta cerebral deposition in cognitively normal individuals. Alzheimers Dement (Amst) 2017 Sep 12;8:179–187. doi: 10.1016/j. dadm.2017.07.004. eCollection;%2017.:179–187.Google Scholar
  21. 21.
    Ovod V, Ramsey KN, Mawuenyega KG, et al. Amyloid beta concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 2017 Aug;13:841–849.Google Scholar
  22. 22.
    Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid–beta biomarkers for Alzheimer’s disease. Nature 2018 Feb 8;554:249–254.CrossRefPubMedGoogle Scholar
  23. 23.
    Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment, 4th Edition ed. New York: Oxofrd University Press, 2004.Google Scholar
  24. 24.
    Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004 Sep;256:183–194.Google Scholar
  25. 25.
    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition ed. Washington D.C.: American Psychiatric Association, 2000.Google Scholar
  26. 26.
    Jagust W, Reed B, Mungas D, Ellis W, Decarli C. What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia? Neurology 2007 Aug 28;69:871–877.CrossRefPubMedGoogle Scholar
  27. 27.
    Espinosa A, Alegret M, Pesini P, et al. Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable–Amnestic Mild Cognitive Impairment–Storage Subtype. J Alzheimers Dis 2017;57:447–459.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Nordberg A, Carter SF, Rinne J, et al. A European multicentre PET study of fibrillar amyloid in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 2013 Jan;40:104–114.Google Scholar
  29. 29.
    Perez–Grijalba V, Fandos N, Canudas J, et al. Validation of Immunoassay–Based Tools for the Comprehensive Quantification of Abeta40 and Abeta42 Peptides in Plasma. J Alzheimers Dis 2016 Aug 10;54:751–762.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Perez–Grijalba V, Pesini P, Allue JA, et al. Abeta1–17 is a major amyloid–beta fragment isoform in cerebrospinal fluid and blood with possible diagnostic value in Alzheimer’s disease. J Alzheimers Dis 2015;43:47–56.CrossRefPubMedGoogle Scholar
  31. 31.
    Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990 Mar;31:545–548.Google Scholar
  32. 32.
    van OM, Hofman A, Soares HD, Koudstaal PJ, Breteler MM. Plasma Abeta(1–40) and Abeta(1–42) and the risk of dementia: a prospective case–cohort study. Lancet Neurol 2006 Aug;5:655–660.Google Scholar
  33. 33.
    Abdullah L, Luis C, Paris D, et al. Serum Abeta levels as predictors of conversion to mild cognitive impairment/Alzheimer disease in an ADAPT subcohort. Mol Med 2009 Nov;15:432–437.Google Scholar
  34. 34.
    Yaffe K, Weston A, Graff–Radford NR, et al. Association of plasma betaamyloid level and cognitive reserve with subsequent 19;305:261–266.Google Scholar
  35. 35.
    Okereke OI, Xia W, Selkoe DJ, Grodstein F. Ten–year change in plasma amyloid beta levels and late–life cognitive decline. Arch Neurol 2009 Oct;66:1247–1253.Google Scholar
  36. 36.
    Koyama A, Okereke OI, Yang T, Blacker D, Selkoe DJ, Grodstein F. Plasma amyloid–beta as a predictor of dementia and cognitive decline: a systematic review and meta–analysis. Arch Neurol 2012 Jul;69:824–831.Google Scholar
  37. 37.
    Rembach A, Watt AD, Wilson WJ, et al. Plasma amyloid–beta levels are significantly associated with a transition toward Alzheimer’s disease as measured by cognitive decline and change in neocortical amyloid burden. J Alzheimers Dis 2014;40:95–104.CrossRefPubMedGoogle Scholar
  38. 38.
    Janelidze S, Stomrud E, Palmqvist S, et al. Plasma beta–amyloid in Alzheimer’s disease and vascular disease. Sci Rep 2016 May 31;6:26801. doi: 10.1038/srep26801.:26801.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Shaw LM, Vanderstichele H, Knapik–Czajka M, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 2009 Apr;65:403–413.Google Scholar
  40. 40.
    Toledo JB, Vanderstichele H, Figurski M, et al. Factors affecting Abeta plasma levels and their utility as biomarkers in ADNI. Acta Neuropathol 2011 Oct;122:401–413.Google Scholar
  41. 41.
    Vanderstichele H, Van KE, Hesse C, et al. Standardization of measurement of beta–amyloid(1–42) in cerebrospinal fluid and plasma. Amyloid 2000 Dec;7:245–258.Google Scholar
  42. 42.
    Roher AE, Esh CL, Kokjohn TA, et al. Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer’s disease. Alzheimers Dement 2009 Jan;5:18–29.Google Scholar
  43. 43.
    Poljak A, Crawford JD, Smythe GA, et al. The Relationship Between Plasma Abeta Levels, Cognitive Function and Brain Volumetrics: Sydney Memory and Ageing Study. Curr Alzheimer Res 2016;13:243–255.CrossRefPubMedGoogle Scholar
  44. 44.
    Figurski MJ, Waligorska T, Toledo J, et al. Improved protocol for measurement of plasma beta–amyloid in longitudinal evaluation of Alzheimer’s Disease Neuroimaging Initiative study patients. Alzheimers Dement 2012 Jul;8:250–260.Google Scholar
  45. 45.
    Insel PS, Mattsson N, Mackin RS, et al. Biomarkers and cognitive endpoints to optimize trials in Alzheimer’s disease. Ann Clin Transl Neurol 2015 May;2:534–547.Google Scholar

Copyright information

© Serdi and Springer Nature Switzerland AG 2018

Authors and Affiliations

  • V. Pérez-Grijalba
    • 1
  • J. Romero
    • 1
  • Pedro Pesini
    • 1
    • 7
  • L. Sarasa
    • 1
  • I. Monleón
    • 1
  • I. San-José
    • 1
  • J. Arbizu
    • 2
  • P. Martínez-Lage
    • 3
  • J. Munuera
    • 4
  • A. Ruiz
    • 5
  • L. Tárraga
    • 5
  • M. Boada
    • 5
  • M. Sarasa
    • 1
  • The AB255 Study Group
    • 6
  1. 1.Araclon Biotech S.LZaragozaSpain
  2. 2.Servicio de Medicina NuclearClínica Universidad de NavarraPamplonaSpain
  3. 3.Center for Research and Advanced Therapies and Memory ClinicFundación CITA-AlzheimerSan SebastiánSpain
  4. 4.Institut de recerca Sant Joan de DéuHospital Infantil Sant Joan de DéuBarcelonaSpain
  5. 5.Alzheimer Research Center and Memory Clinic. Fundació ACE. Institut Català de Neurociències AplicadesBarcelonaSpain
  6. 6.
  7. 7.ZaragozaSpain

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