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Factors affecting Aβ plasma levels and their utility as biomarkers in ADNI

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Abstract

Previous studies of Aβ plasma as a biomarker for Alzheimer’s disease (AD) obtained conflicting results. We here included 715 subjects with baseline Aβ1-40 and Aβ1-42 plasma measurement (50% with 4 serial annual measurements): 205 cognitively normal controls (CN), 348 patients mild cognitive impairment (MCI) and 162 with AD. We assessed the factors that modified their concentrations and correlated these values with PIB PET, MRI and tau and Aβ1-42 measures in cerebrospinal fluid (CSF). Association between Aβ and diagnosis (baseline and prospective) was assessed. A number of health conditions were associated with altered concentrations of plasma Aβ. The effect of age differed according to AD stage. Plasma Aβ1-42 showed mild correlation with other biomarkers of Aβ pathology and were associated with infarctions in MRI. Longitudinal measurements of Aβ1-40 and Aβ1-42 plasma levels showed modest value as a prognostic factor for clinical progression. Our longitudinal study of complementary measures of Aβ pathology (PIB, CSF and plasma Aβ) and other biomarkers in a cohort with an extensive neuropsychological battery is significant because it shows that plasma Aβ measurements have limited value for disease classification and modest value as prognostic factors over the 3-year follow-up. However, with longer follow-up, within subject plasma Aβ measurements could be used as a simple and minimally invasive screen to identify those at increased risk for AD. Our study emphasizes the need for a better understanding of the biology and dynamics of plasma Aβ as well as the need for longer term studies to determine the clinical utility of measuring plasma Aβ.

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References

  1. (1998) 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. Neurobiology of aging 19(2): 109–116

  2. Alexander G, Furey M, Grady C et al (1997) Association of premorbid intellectual function with cerebral metabolism in Alzheimer’s disease: implications for the cognitive reserve hypothesis. Am J Psychiatry 154(2):165–172

    PubMed  CAS  Google Scholar 

  3. Arvanitakis Z, Lucas JA, Younkin LH, Younkin SG, Graff-Radford NR (2002) Serum creatinine levels correlate with plasma amyloid [beta] protein. Alzheimer Dis Assoc Disord 16(3):187–190

    Article  PubMed  CAS  Google Scholar 

  4. Blasko I, Kemmler G, Krampla W et al (2005) Plasma amyloid [beta] protein 42 in non-demented persons aged 75 years: effects of concomitant medication and medial temporal lobe atrophy. Neurobiol Aging 26(8):1135–1143

    Article  PubMed  CAS  Google Scholar 

  5. Blennow K, De Meyer G, Hansson O et al (2009) Evolution of Abeta42 and Abeta40 levels and Abeta42/Abeta40 ratio in plasma during progression of Alzheimer’s disease: a multicenter assessment. J Nutr Health Aging 13(3):205–208

    Article  PubMed  CAS  Google Scholar 

  6. Butters N, Granholm E, Salmon D, Grant I, Wolfe J (1987) Episodic and semantic memory: a comparison of amnesic and demented patients. J Clin Exp Neuropsychol 9(5):479–497

    Article  PubMed  CAS  Google Scholar 

  7. Carmichael O, Schwarz C, Drucker D et al (2010) Longitudinal changes in white matter disease and cognition in the first year of the alzheimer disease neuroimaging initiative. Arch Neurol 67(11):1370–1378

    Article  PubMed  Google Scholar 

  8. Cosentino SA, Stern Y, Sokolov E et al (2010) Plasma {beta}-amyloid and cognitive decline. Arch Neurol 67(12):1485–1490

    Article  PubMed  Google Scholar 

  9. Chen M, Inestrosa NC, Ross GS, Fernandez HL (1995) Platelets are the primary source of amyloid [beta]-peptide in human blood. Biochem Biophys Res Commun 213(1):96–103

    Article  PubMed  CAS  Google Scholar 

  10. Davatzikos C, Bhatt P, Shaw LM, Batmanghelich KN and Trojanowski JQ (2010) Prediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification. Neurobiol aging

  11. de Souza LC, Lamari F, Belliard S et al (2011) Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer’s disease from other cortical dementias. J Neurol Neurosurg Psychiatry 82(3):240–246

    Article  PubMed  Google Scholar 

  12. Devanand DP, Schupf N, Stern Y et al (2011) Plasma Aβ and PET PiB binding are inversely related in mild cognitive impairment. Neurology

  13. Fagan AM, Mintun MA, Shah AR et al (2009) Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. EMBO Mol Med 1(8–9):371–380

    Article  PubMed  CAS  Google Scholar 

  14. Fagan AM, Shaw LM, Xiong C et al (2011) Comparison of Analytical Platforms for Cerebrospinal Fluid Measures of {beta}-Amyloid 1-42, Total tau, and P-tau181 for Identifying Alzheimer Disease Amyloid Plaque Pathology. Arch Neurol

  15. Fei M, Jianghua W, Rujuan M, Wei Z, Qian W (2011) The relationship of plasma A[beta] levels to dementia in aging individuals with mild cognitive impairment. J Neurol Sci 305(1–2):92–96

    Article  PubMed  Google Scholar 

  16. Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198

    Article  PubMed  CAS  Google Scholar 

  17. Fukumoto H, Tennis M, Locascio JJ et al (2003) Age but not diagnosis is the main predictor of plasma amyloid {beta}-protein levels. Arch Neurol 60(7):958–964

    Article  PubMed  Google Scholar 

  18. Goldberg KM, Iglewicz B (1992) Bivariate extensions of the boxplot. Technometrics 34:307–320

    Article  Google Scholar 

  19. Goodglass H, Kaplan E (1983) The assessment of aphasia and related disorders. Lea & Febiger, Philadelphia

    Google Scholar 

  20. Graff-Radford NR, Crook JE, Lucas J et al (2007) Association of low plasma Abeta42/Abeta40 Ratios with increased imminent risk for mild cognitive impairment and alzheimer disease. Arch Neurol 64(3):354–362

    Article  PubMed  Google Scholar 

  21. Gurol ME, Irizarry MC, Smith EE et al (2006) Plasma β-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology 66(1):23–29

    Article  PubMed  CAS  Google Scholar 

  22. Ikonomovic MD, Klunk WE, Abrahamson EE et al (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 131(6):1630–1645

    Article  PubMed  Google Scholar 

  23. Jack CR Jr, Bernstein MA, Fox NC et al (2008) The Alzheimer’s disease neuroimaging initiative (ADNI): MRI methods. J Magn Reson Imaging 27(4):685–691

    Article  PubMed  Google Scholar 

  24. Jack CR Jr, Knopman DS, Jagust WJ et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9(1):119–128

    Article  PubMed  CAS  Google Scholar 

  25. Jagust WJ, Bandy D, Chen K et al (2010) The Alzheimer’s disease neuroimaging Initiative positron emission tomography core. Alzheimers Dement 6(3):221–229

    Article  PubMed  Google Scholar 

  26. Kaplan E, Goodglass H, Weintraub S (1983) Boston naming test. Lea & Febiger, Philadelphia

    Google Scholar 

  27. Lachno DR, Vanderstichele H, De Groote G et al (2009) The influence of matrix type, diurnal rhythm and sample collection and processing on the measurement of plasma beta-amyloid isoforms using the INNO-BIA plasma Abeta forms multiplex assay. J Nutr Health Aging 13(3):220–225

    Article  PubMed  CAS  Google Scholar 

  28. Lambert J-C, Schraen-Maschke S, Richard F et al (2009) Association of plasma amyloid β with risk of dementia. Neurology 73(11):847–853

    Article  PubMed  CAS  Google Scholar 

  29. Lambert JC, Dallongeville J, Ellis KA et al (2011) Association of plasma aβ peptides with blood pressure in the elderly. PLoS ONE 6(4):e18536

    Article  PubMed  CAS  Google Scholar 

  30. Laske C, Sopova K, Gkotsis C et al (2010) Amyloid-β peptides in plasma and cognitive decline after 1 year follow-up in alzheimer’s disease patients. J Alzheimers Dis 21(4):1263–1269

    PubMed  CAS  Google Scholar 

  31. Lewczuk P, Kornhuber J, Vanmechelen E et al (2010) Amyloid beta peptides in plasma in early diagnosis of Alzheimer’s disease: a multicenter study with multiplexing. Exp Neurol 223(2):366–370

    Article  PubMed  CAS  Google Scholar 

  32. Locascio JJ, Fukumoto H, Yap L et al (2008) Plasma amyloid {beta}-protein and c-reactive protein in relation to the rate of progression of Alzheimer disease. Arch Neurol 65(6):776–785

    Article  PubMed  Google Scholar 

  33. Lopez OL, Kuller LH, Mehta PD et al (2008) Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study. Neurology 70(19):1664–1671

    Article  PubMed  CAS  Google Scholar 

  34. Lui JK, Laws SM, Li Q-X et al (2010) Plasma amyloid-β as a biomarker in Alzheimer’s disease: the AIBL study of aging. J Alzheimers Dis 20(4):1233–1242

    PubMed  CAS  Google Scholar 

  35. Mathis CA, Wang Y, Holt DP et al (2003) Synthesis and Evaluation of 11C-Labeled 6-Substituted 2-Arylbenzothiazoles as Amyloid Imaging Agents. J Med Chem 46(13):2740–2754

    Article  PubMed  CAS  Google Scholar 

  36. Mayeux R, Tang M-X, Jacobs DM et al (1999) Plasma amyloid β-peptide 1-42 and incipient Alzheimer’s disease. Ann Neurol 46(3):412–416

    Article  PubMed  CAS  Google Scholar 

  37. Mayeux R, Honig LS, Tang M-X et al (2003) Plasma Aβ40 and Aβ42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology 61(9):1185–1190

    PubMed  CAS  Google Scholar 

  38. Mehta PD, Pirttila T, Patrick BA, Barshatzky M, Mehta SP (2001) Amyloid [beta] protein 1-40 and 1-42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett 304(1–2):102–106

    Article  PubMed  CAS  Google Scholar 

  39. Petersen RC, Aisen PS, Beckett LA et al (2010) Alzheimer’s disease neuroimaging initiative (ADNI): clinical characterization. Neurology 74(3):201–209

    Article  PubMed  Google Scholar 

  40. R Development Core Team (2010) R: A language and environment for statistical computing R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0. http://www.R-project.org/

  41. Reitan R (1958) Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 8:271–276

    Google Scholar 

  42. Rentz DM, Locascio JJ, Becker JA et al (2010) Cognition, reserve, and amyloid deposition in normal aging. Ann Neurol 67(3):353–364

    Article  PubMed  Google Scholar 

  43. Rey A (1964) L’examen clinique en psychologie. Presses Universitaires de France, Paris

    Google Scholar 

  44. Rosen W, Mohs R, Davis K (1984) A new rating scale for Alzheimer’s disease. Am J Psychiatry 141(11):1356–1364

    PubMed  CAS  Google Scholar 

  45. Ryan JR, Paolo AM (1992) A screening procedure for estimating premorbid intelligence in the elderly. Clin Neuropsychol 6(1):53–62

    Article  Google Scholar 

  46. Schupf N, Tang MX, Fukuyama H et al (2008) Peripheral Aβ subspecies as risk biomarkers of Alzheimer’s disease. Proc Nat Acad Sci 105(37):14052–14057

    Article  PubMed  CAS  Google Scholar 

  47. Schupf N, Zigman WB, Tang M-X et al (2010) Change in plasma Aβ peptides and onset of dementia in adults with Down syndrome. Neurology 75(18):1639–1644

    Article  PubMed  CAS  Google Scholar 

  48. Seppälä TT, Herukka S-K, Hänninen T et al (2010) Plasma Aβ42 and Aβ40 as markers of cognitive change in follow-up: a prospective, longitudinal, population-based cohort study. J Neurol Neurosurg Psychiatry 81(10):1123–1127

    Article  PubMed  Google Scholar 

  49. Shaw LM, Vanderstichele H, Knapik-Czajka M et al (2009) Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 65(4):403–413

    Article  PubMed  CAS  Google Scholar 

  50. Shaw LM, Vanderstichele H, Knapik-Czajka M et al (2011) Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol 121(5):597–609

    Article  PubMed  CAS  Google Scholar 

  51. Song F, Poljak A, Valenzuela M, et al (2011) Meta-Analysis of Plasma Amyloid-beta levels in Alzheimer’s Disease. J Alzheimers Dis (1875-8908 (Electronic))

  52. Sundelof J, Giedraitis V, Irizarry MC et al (2008) Plasma beta amyloid and the risk of alzheimer disease and dementia in elderly men: a prospective, population-based cohort study. Arch Neurol 65(2):256–263

    Article  PubMed  Google Scholar 

  53. Taylor K, Salmon D, Rice V et al (1996) Longitudinal examination of american national adult reading test (AMNART) performance in dementia of the Alzheimer type (DAT): validation and correction based on degree of cognitive decline. J Clin Exp Neuropsychol 18(6):883–891

    Article  PubMed  CAS  Google Scholar 

  54. Van Dijk EJ, Prins ND, Vermeer SE et al (2004) Plasma amyloid β, apolipoprotein E, lacunar infarcts, and white matter lesions. Ann Neurol 55(4):570–575

    Article  PubMed  Google Scholar 

  55. van Oijen M, Hofman A, Soares HD, Koudstaal PJ, Breteler MM (2006) Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol 5(8):655–660

    Article  PubMed  Google Scholar 

  56. Wechsler D (1987) Wechsler Memory Scale. Rev ed. Psychological Corp, San Antonio

  57. Weigand SD, Vemuri P, Wiste HJ et al (2011) Transforming cerebrospinal fluid Abeta42 measures into calculated Pittsburgh compound B units of brain Abeta amyloid. Alzheimers Dement 7(2):133–141

    Article  PubMed  CAS  Google Scholar 

  58. Wilcox RR, Schönbrodt FD (2009) The WRS package for robust statistics in R (version 0.12.1). http://r-forge.r-project.org/projects/wrs/

  59. Yaffe K, Weston A, Graff-Radford NR et al (2011) Association of plasma β-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA 305(3):261–266

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank our ADNI colleagues for their contributions to the work summarized here which has been supported mainly by the ADNI U01 AG024904. ADNI is funded by the National Institute of Aging, the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the Foundation for the National Institutes of Health, through generous contributions from the following companies and organizations: Pfizer Inc., Wyeth Research, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck & Co. Inc., AstraZeneca AB, Novartis Pharmaceuticals Corporation, the Alzheimer’s Association, Eisai Global Clinical Development, Elan Corporation plc, Forest Laboratories, and the Institute for the Study of Aging (ISOA), with participation from the U.S. Food and Drug Administration. Other support has come from AG10124 and the Marian S. Ware Alzheimer Program. VMYL is the John H. Ware 3rd Professor for Alzheimer’s Disease Research and JQT is the William Maul Measy-Truman G. Schnabel Jr. M.D. Professor of Geriatric Medicine and Gerontology. We thank the ADNI Biomarker Core for the analyses. We thank Donald Baldwin and the Molecular Diagnosis Genotyping Facility at the University of Pennsylvania Medical Center for provision of the APOε genotyping data. J.B.T.’s work was supported by a grant from the Alfonso Martín Escudero foundation. L.S.’s, C.J.’s and M.W.’s work is partially supported by NIH.

Conflict of interest

J.Q.T., V.M.Y.L., A.W.T., S.X.X., E.T., M.F., M.W., C.J., P.A., W.J. and J.B.T. have no conflicts of interest. L.S. belongs to the advisory board of Innogenetics Technical. H.V. works at INNX-Fujirebio.

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Correspondence to John Q. Trojanowski or Leslie M. Shaw.

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Toledo, J.B., Vanderstichele, H., Figurski, M. et al. Factors affecting Aβ plasma levels and their utility as biomarkers in ADNI. Acta Neuropathol 122, 401–413 (2011). https://doi.org/10.1007/s00401-011-0861-8

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