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Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-β changes occur before increases of tau in cerebrospinal fluid

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Abstract

In comparison to the levels in age and gender-matched controls, reduced levels of pathological amyloid-β protein in cerebrospinal fluid routinely precede the onset of Alzheimer’s disease-related symptoms by several years, whereas elevated soluble abnormal tau fractions (phosphorylated tau, total tau protein) in cerebrospinal fluid are detectable only with the onset and progression of clinical symptoms. This sequence of events in cerebrospinal fluid (amyloid-β changes detectable prior to abnormal tau changes) contrasts with that in which both proteins develop in the brain, where intraneuronal tau inclusions (pretangles, neurofibrillary tangles, neuropil threads) appear decades before the deposition of amyloid-β plaques (diffuse plaques, neuritic plaques). This viewpoint attempts to address questions arising in connection with this apparent sequential discrepancy—questions and issues for which there are currently no clear-cut answers.

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References

  1. Albert MS, Dekosky ST, Dickson D et al (2011) 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 7:270–279

    PubMed  Google Scholar 

  2. Alonso AC, Li B, Grundke-Iqbal I et al (2008) Mechanism of tau-induced neurodegeneration in Alzheimer disease and related tauopathies. Curr Alzheimer Res 5:375–384

    PubMed  CAS  Google Scholar 

  3. Amieva H, le Goff M, Millet X et al (2008) Prodromal Alzheimer’s disease: successive emergence of clinical symptoms. Ann Neurol 64:492–498

    PubMed  Google Scholar 

  4. Andreasen N, Hesse C, Davidsson P et al (1999) Cerebrospinal fluid β-amyloid(1–42) in Alzheimer’s disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol 56:673–680

    PubMed  CAS  Google Scholar 

  5. Andreasen N, Minthon L, Vanmechelen E et al (1999) Cerebrospinal fluid tau and Abeta42 as predictors of development of Alzheimer’s disease in patients with mild cognitive impairment. Neurosci Lett 273:5–8

    PubMed  CAS  Google Scholar 

  6. Arai H, Terajima M, Miura M et al (1995) Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer’s disease. Ann Neurol 38:649–652

    PubMed  CAS  Google Scholar 

  7. Arnold SE, Hyman BT, Flory J et al (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cerebr Cortex 1:103–116

    CAS  Google Scholar 

  8. Baas PW (2002) Microtubule transport in the axon. Int Rev Cytol 212:41–62

    PubMed  CAS  Google Scholar 

  9. Ballatore C, Lee VMY, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nature Rev Neurosci 8:663–672

    CAS  Google Scholar 

  10. Bancher C, Brunner C, Lassmann H et al (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477:90–99

    PubMed  CAS  Google Scholar 

  11. Bateman RJ, Xiong C, Benzinger TL, Dominantly Inherited Alzheimer Network et al (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804

    PubMed  CAS  Google Scholar 

  12. Blennow K (2004) Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx 1:213–225

    PubMed  Google Scholar 

  13. Blennow K, Hampel H (2003) Cerebrospinal fluid markers for incipient Alzheimer’s disease. Lancet Neurol 2:605–613

    PubMed  CAS  Google Scholar 

  14. Blennow K, Wallin A, Agren H et al (1995) Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 26:231–245

    PubMed  CAS  Google Scholar 

  15. Blennow K, Zetterberg H, Minthon L et al (2007) Longitudinal stability of CSF biomarkers in Alzheimer’s disease. Neurosci Lett 419:18–22

    PubMed  CAS  Google Scholar 

  16. Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144

    PubMed  CAS  Google Scholar 

  17. Blennow K, Hardy J, Zetterberg H (2012) The neuropathology and neurobiology of traumatic brain injury. Neuron 76:886–899

    PubMed  CAS  Google Scholar 

  18. Blennow K, Zetterberg H, Fagan AM (2012) Fluid biomarkers in Alzheimer’s disease. Cold Spring Harb Perspect Med 2:a006221

    PubMed  Google Scholar 

  19. Blom ES, Giedraitis V, Zetterberg H et al (2009) Rapid progression from mild cognitive impairment to Alzheimer’s disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE epsilon4/epsilon4 genotype. Dement Geriatr Cogn Disord 27:458–464

    PubMed  CAS  Google Scholar 

  20. Bobinski M, Wegiel J, Tarnawski M et al (1998) Duration of neurofibrillary changes in the hippocampal pyramidal neurons. Brain Res 799:156–158

    PubMed  CAS  Google Scholar 

  21. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    PubMed  CAS  Google Scholar 

  22. Braak H, del Tredici K (2004) Alzheimer’s disease: intraneuronal alterations precede insoluble amyloid-β formation. Neurobiol Aging 25:713–718

    PubMed  Google Scholar 

  23. Braak H, del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181

    PubMed  Google Scholar 

  24. Braak H, del Tredici K (2012) Alzheimer’s disease: pathogenesis and prevention. Alzheimers Dement 8:227–233

    PubMed  CAS  Google Scholar 

  25. Braak H, del Tredici K (2012) Where, when, and in what form does sporadic Alzheimer’s disease begin? Curr Opin Neurol 25:708–714

    PubMed  CAS  Google Scholar 

  26. Braak H, del Tredici K (2013) Evolutional aspects of Alzheimer’s disease pathogenesis. J Alzheimer Dis 30(Suppl 1):155–161

    Google Scholar 

  27. Braak H, Thal DR, Ghebremedhin E et al (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969

    PubMed  CAS  Google Scholar 

  28. Buchhave P, Minthon L, Zetterberg H et al (2012) Cerebrospinal fluid levels of β-amyloid 1–42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry 69:98–106

    PubMed  CAS  Google Scholar 

  29. Buerger K, Ewers M, Pirttilä T et al (2006) CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain 129:3035–3041

    PubMed  Google Scholar 

  30. Cowan CM, Bossing T, Page A et al (2010) Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo. Acta Neuropathol 120:593–604

    PubMed  CAS  Google Scholar 

  31. Degerman Gunnarsson M, Lindau M, Wall A et al (2010) Pittsburgh Compound-B and Alzheimer’s disease biomarkers in CSF, plasma and urine: an exploratory study. Dement Geriatr Cogn Disord 29:204–212

    PubMed  CAS  Google Scholar 

  32. Dolan D, Troncoso J, Resnick SM et al (2010) Age, Alzheimer’s disease and dementia in the Baltimore Longitudinal Study of Ageing. Brain 133:2225–2231

    PubMed  Google Scholar 

  33. Dong S, Duan Y, Hu Y, Zhao Z (2012) Advances in the pathogenesis of Alzheimer’s disease: a re-evaluation of amyloid cascade hypothesis. Transl Neurodegener 1:1–12

    Google Scholar 

  34. Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer’s disease. Acta Neuropathol 118:5–36

    PubMed  CAS  Google Scholar 

  35. Elobeid A, Soininen H, Alafuzoff I (2011) Hyperphosphorylated tau in young and middle-aged subjects. Acta Neuropathol 123:97–104

    PubMed  Google Scholar 

  36. Fagan AM, Mintun MA, Mach RH et al (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59:512–519

    PubMed  CAS  Google Scholar 

  37. Fagan AM, Roe CM, Xiong C et al (2007) Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 64:343–349

    PubMed  Google Scholar 

  38. Fewster PH, Griffin-Brooks S, MacGregor J et al (1991) A topographical pathway by which histopathological lesions disseminate through the brain of patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2:121–132

    Google Scholar 

  39. Fillenbaum GG, van Belle G, Morris JC et al (2008) CERAD (Consortium to establish a registry for Alzheimer’s disease) The first 20 years. Alzheimers Dement 4:96–109

    PubMed  Google Scholar 

  40. Fodero-Tavoletti MT, Okamura N, Furumoto S et al (2011) 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer’s disease. Brain 134:1089–1100

    PubMed  Google Scholar 

  41. Galvan V, Gorostiza OF, Banweit S et al (2006) Reversal of Alzheimer’s-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci USA 103:7130–7135

    PubMed  CAS  Google Scholar 

  42. Giannakopoulos P, Herrmann FR, Bussiere T et al (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60:1495–1500

    PubMed  CAS  Google Scholar 

  43. Goedert M, Klug A, Crowther RA (2006) Tau protein, the paired helical filament and Alzheimer’s disease. J Alzheimers Dis 9(Suppl):195–207

    PubMed  CAS  Google Scholar 

  44. Grimmer T, Henriksen G, Wester HJ et al (2009) Clinical severity of Alzheimer’s disease is associated with PiB uptake in PET. Neurobiol Aging 30:1902–1909

    PubMed  CAS  Google Scholar 

  45. Grimmer T, Riemenschneider M, Förstl H et al (2009) Beta amyloid in Alzheimer’s disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid. Biol Psychiatry 65:927–934

    PubMed  CAS  Google Scholar 

  46. Guillozet AL, Weintraub S, Mash DC et al (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729–736

    PubMed  Google Scholar 

  47. Gustafson DR, Skoog I, Rosengren L et al (2007) Cerebrospinal fluid β-amyloid 1–42 concentration may predict cognitive decline in older women. J Neurol Neurosurg Psychiatry 78:461–464

    PubMed  Google Scholar 

  48. Hall GF (2012) The biology and pathobiology of tau protein. In: Kavallaris M (ed) The cytoskeleton and human disease. Springer, New York, pp 285–313

    Google Scholar 

  49. Hall GF, Saman S (2012) Death or secretion? The demise of a plausible assumption about CSF-tau in Alzheimer disease? Commun Integrat Biol 5:1–4

    Google Scholar 

  50. Hardy JA (2006) Alzheimer’s disease: the amyloid cascade hypothesis: an update and reappraisal. J Alzheimers Dis 9:151–153

    PubMed  CAS  Google Scholar 

  51. Hardy JA, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    PubMed  CAS  Google Scholar 

  52. Hesse C, Rosengren L, Vanmechelen E et al (2000) Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. J Alzheimer Dis 2:199–206

    CAS  Google Scholar 

  53. Hesse C, Rosengren L, Andreasen N et al (2001) Transient increase in CSF total tau but not phospho-tau after acute stroke. Neurosci Lett 297:187–190

    PubMed  CAS  Google Scholar 

  54. Hyman BT, Goméz-Isla T (1994) Alzheimer’s disease is a laminar, regional, and neural system specific disease, not a global brain disease. Neurobiol Aging 15:353–354

    PubMed  CAS  Google Scholar 

  55. Hyman BT, Phelps CH, Beach TG et al (2012) National institute on aging-Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alheimers Dement 8:1–13

    Google Scholar 

  56. 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 131:1630–1645

    PubMed  Google Scholar 

  57. Iqbal K, Grundke-Iqbal I (2008) Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention. J Cell Mol Med 12:38–55

    PubMed  CAS  Google Scholar 

  58. Iqbal K, Liu F, Gong CX et al (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118:53–69

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  60. Jack CR Jr, Knopman DS, Jagust WJ et al (2013) Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12:207–216

    PubMed  CAS  Google Scholar 

  61. Jeganathan S, von Bergen M, Mandelkow EM et al (2008) The natively unfolded character of tau and its aggregation to Alzheimer-like paired helical filaments. Biochemistry 47:10526–10539

    PubMed  CAS  Google Scholar 

  62. Jensen JR, Cisek K, Funk KE et al (2011) Research towards tau imaging. J Alzheimers Dis 26(Suppl 3):147–157

    PubMed  Google Scholar 

  63. Karran E, Mercken M, de Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712

    PubMed  CAS  Google Scholar 

  64. Klunk WE, Engler H, Nordberg A et al (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306–319

    PubMed  CAS  Google Scholar 

  65. Korczyn AD (2008) The amyloid cascade hypothesis. Alzheimers Dement 4:176–178

    PubMed  CAS  Google Scholar 

  66. Kovacech B, Skrabana R, Novak M (2010) Transition of tau protein from disordered to misordered in Alzheimer’s disease. Neurodegener Dis 7:24–27

    PubMed  CAS  Google Scholar 

  67. Le S, Kim W, Li Z, McKee AC, Hall GF (2012) Accumulation of vesicle-associated human tau in distal dendrites drives degeneration and tau secretion in an in situ cellular tauopathy model. Int J Alzheimers Dis 2012:172837. doi:10.1155/2012/172837

    Google Scholar 

  68. Lee HG, Casadesus G, Zhu X et al (2004) Perspectives on the amyloid-beta cascade hypothesis. J Alzheimers Dis 6:137–145

    PubMed  CAS  Google Scholar 

  69. Lee HG, Zhu K, Castellani RJ et al (2007) Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther 321:823–829

    PubMed  CAS  Google Scholar 

  70. Li B, Chohan MO, Grundke-Iqbal I et al (2007) Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau. Acta Neuropathol 113:501–511

    PubMed  CAS  Google Scholar 

  71. Liu F, Xue ZQ, Deng SH, et al (2013) γ-Secretase binding sites in aged and Alzheimer’s disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ. Eur J Neurosci 12159 [Epub ahead of print]. doi:10.1111/ejn

  72. Mandelkow EM, Mandelkow E (2012) Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med 2:a006247

    PubMed  Google Scholar 

  73. Mandelkow E, von Bergen M, Biernat J et al (2007) Structural principles of tau and the paired helical filaments of Alzheimer’s disease. Brain Pathol 17:83–90

    PubMed  CAS  Google Scholar 

  74. Markesbery WR, Schmitt FA, Kryscio RJ et al (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38–46

    PubMed  Google Scholar 

  75. Masters CL, Selkoe DJ (2012) Biochemistry of amyloid β-protein and amyloid deposits in Alzheimer disease. Cold Spring Harb Perspect Med 2:a006262

    PubMed  Google Scholar 

  76. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639

    PubMed  CAS  Google Scholar 

  77. Mattsson N, Zetterberg H, Hansson O et al (2009) CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302:385–393

    PubMed  CAS  Google Scholar 

  78. Mattsson N, Portelius E, Rolstad S et al (2012) Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment. J Alzheimers Dis 30:767–778

    PubMed  CAS  Google Scholar 

  79. McKee A, Stein TD, Nowinski CJ et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64

    PubMed  Google Scholar 

  80. Mirra S, Heyman A, McKeel D et al (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  81. Montine TJ, Phelps CH, Beach TG et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11

    PubMed  CAS  Google Scholar 

  82. Moonis M, Swearer JM, Dayaw MP et al (2005) Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline. Neurology 65:323–325

    PubMed  CAS  Google Scholar 

  83. Morsch R, Simon W, Coleman PD (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 58:188–197

    PubMed  CAS  Google Scholar 

  84. Motter R, Vigo-Pelfrey C, Kholodenko D et al (1995) Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 38:643–648

    PubMed  CAS  Google Scholar 

  85. Nelson PT, Jicha GA, Schmitt FA et al (2007) Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J Neuropathol Exp Neurol 66:1136–1146

    PubMed  Google Scholar 

  86. Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer’s disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68:1–14

    PubMed  CAS  Google Scholar 

  87. Nelson PT, Head E, Schmitt FA et al (2011) Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies. Acta Neuropathol 121:571–587

    PubMed  Google Scholar 

  88. Nelson PT, Alafuzoff I, Bigio EH et al (2012) Correlation of Alzheimer’s disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381

    PubMed  Google Scholar 

  89. Neselius S, Brisby H, Theodorsson A et al (2012) CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma. PLoS ONE 7(4):e33606

    PubMed  CAS  Google Scholar 

  90. Olsson A, Vanderstichele H, Andreasen N et al (2005) Simultaneous measurement of β-amyloid(1–42), tau and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 51:336–345

    PubMed  CAS  Google Scholar 

  91. Öst M, Nylén K, Csajbok L, Olsson Öhrfelt A et al (2006) Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 67:1600–1604

    PubMed  Google Scholar 

  92. Otto M, Wiltfang J, Tumani H et al (1997) Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 225:210–212

    PubMed  CAS  Google Scholar 

  93. Pimplikar SW (2009) Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int J Biochem Cell Biol 41:1261–1268

    PubMed  CAS  Google Scholar 

  94. Pooler AM, Phillips EC, Lau DHW et al (2013) Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep 14:389–394

    PubMed  CAS  Google Scholar 

  95. Rajendran L, Annaert W (2012) Membrane trafficking pathways in Alzheimer’s disease. Traffic 13:759–770

    PubMed  CAS  Google Scholar 

  96. Ringman JM, Younkin SG, Pratico D et al (2008) Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 71:85–92

    PubMed  CAS  Google Scholar 

  97. Ringman JM, Coppola G, Elashoff D et al (2012) Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer’s disease. Dement Geriatr Cogn Disord 33:1–5

    PubMed  CAS  Google Scholar 

  98. Sabbagh MN, Cooper K, DeLange J et al (2010) Functional, global and cognitive decline correlates to accumulation of Alzheimer’s pathology in MCI and AD. Curr Alzheimer Res 7:280–286

    PubMed  CAS  Google Scholar 

  99. Saman S, Kim W, Raya M et al (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287:3842–3849

    PubMed  CAS  Google Scholar 

  100. Sämgård K, Zetterberg H, Blennow K et al (2010) Cerebrospinal fluid total tau as a marker of Alzheimer’s disease intensity. Int J Geriatr Psychiatry 25:403–410

    PubMed  Google Scholar 

  101. Schönheit B, Zarski R, Ohm TG (2004) Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology. Neurobiol Aging 25:697–711

    PubMed  Google Scholar 

  102. Selkoe DJ (1994) Alzheimer’s disease: a central role for amyloid. J Neuropathol Exp Neurol 53:438–447

    PubMed  CAS  Google Scholar 

  103. Selkoe DJ (2004) Aging, amyloid, and Alzheimer’s disease: a perspective in honor of Carl Cotman. Neurochem Res 28:1703–1713

    Google Scholar 

  104. Selkoe DJ, Mandelkow E, Holtzman D (2012) Deciphering Alzheimer disease. Cold Spring Harb Perspect Med 2:1–8

    Google Scholar 

  105. Seubert P, Vigo-Pelfrey C, Esch F et al (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359:325–327

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  107. Siemers ER (2009) How can we recognize “disease modification” effects? J Nutr Health Aging 13:341–343

    PubMed  CAS  Google Scholar 

  108. Skoog I, Davidsson P, Aevarsson O et al (2003) Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dement Geriatr Cogn Disord 15:169–176

    PubMed  CAS  Google Scholar 

  109. Sperling RA, Eisen PS, Beckett LA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292

    PubMed  Google Scholar 

  110. Stomrud E, Hansson O, Blennow K et al (2007) Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy controls. Dement Geriatr Cogn Disord 24:118–124

    PubMed  CAS  Google Scholar 

  111. Strozyk D, Blennow K, White LR, Launer LJ (2003) CSF Aβ 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 60:652–656

    PubMed  CAS  Google Scholar 

  112. Sunderland T, Linker G, Mirza N et al (2003) Decreased beta-amyloid 1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer’s disease. JAMA 289:2094–2103

    PubMed  Google Scholar 

  113. Tapiola T, Alafuzoff I, Herukka SK et al (2009) Cerebrospinal fluid (beta)-amyloid 42 and tau proteins as biomarker changes in the brain. Arch Neurol 66:382–389

    PubMed  Google Scholar 

  114. Tato RE, Frank A, Hernanz A (1995) Tau protein concentrations in cerebrospinal fluid of patients with dementia of the Alzheimer type. J Neurol Neurosurg Psychiatry 59:280–283

    PubMed  CAS  Google Scholar 

  115. Thal DR, Rüb U, Schultz C et al (2000) Sequence of Aβ-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol 59:733–748

    PubMed  CAS  Google Scholar 

  116. Thal DR, Rüb U, Orantes M et al (2002) Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    PubMed  Google Scholar 

  117. Uchihara T (2007) Silver diagnosis in neuropathology: principles, practice and revised interpretation. Acta Neuropathol 113:483–499

    PubMed  Google Scholar 

  118. Uchihara T, Nakamura A, Yamazaki M, Mori O (2001) Evolution from pretangle neurons to neurofibrillary tangles monitored by thiazin red combined with Gallyas method and double immunofluorescence. Acta Neuropathol 101:535–539

    PubMed  CAS  Google Scholar 

  119. Vanderstichele HM, Shaw L, Vandijck M, et al (2013) Alzheimer disease biomarker testing in cerebrospinal fluid: a method to harmonize assay platforms in the absence of an absolute reference standard. Clin Chem 25 January [ahead of print]. doi:10.1373/clinchem.2012.201830

  120. Vandermeeren M, Mercken M, Vanmechelen E et al (1993) Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 61:1828–1834

    PubMed  CAS  Google Scholar 

  121. Vanmechelen E, Vanderstichele H, Davidsson P et al (2000) Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 285:49–52

    PubMed  CAS  Google Scholar 

  122. van Rossum IA, Vos SJB, Burns L et al (2012) Injury markers predict cognitive decline in subjects with MCI and amyloid pathology. Neurology 79:1809–1816

    PubMed  Google Scholar 

  123. Visser PJ, Verhey F, Knol DL et al (2009) Prevalence and prognostic value of cerebrospinal fluid markers of Alzheimer pathology in subjects with subjective cognitive impairment and mild cognitive impairment. The DESCRIPA study. Lancet Neurol 8:619–627

    PubMed  Google Scholar 

  124. Vlassenko AG, Benzinger TL, Morris JC (2012) PET amyloid-beta imaging in preclinical Alzheimer’s disease. Biochim Biophys Acta 1822:370–379

    PubMed  CAS  Google Scholar 

  125. von Bergen M, Barghorn S, Biernat J et al (2005) Tau aggregation is driven by a transition from random coil to beta sheet structure. Biochim Biophys Acta 1739:158–166

    Google Scholar 

  126. Wallin ÅK, Blennow K, Andreasen N, Minthon L (2006) CSF biomarkers for Alzheimer’s disease: levels of β-amyloid, tau and phosphorylated tau relate to clinical symptoms and survival. Dement Geriatr Cogn Disord 21:131–138

    PubMed  CAS  Google Scholar 

  127. Weaver CL, Espinoza M, Kress Y et al (2000) Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol Aging 21:719–727

    PubMed  CAS  Google Scholar 

  128. Zetterberg H, Hietala MA, Jonsson M et al (2006) Neurochemical aftermath of amateur boxing. Arch Neurol 63:1277–1280

    PubMed  Google Scholar 

  129. Zetterberg H, Pedersen M, Lind K et al (2007) Intra-individual stability of CSF biomarkers for Alzheimer’s disease over two years. J Alzheimers Dis 12:255–260

    PubMed  CAS  Google Scholar 

  130. Zetterberg H, Tullhög K, Hansson O et al (2010) Low incidence of post-lumbar puncture headache in 1,089 consecutive memory clinic patients. Eur Neurol 63:326–330

    PubMed  Google Scholar 

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Acknowledgments

The technical assistance of Mr. David Ewert (graphics, University of Ulm) is gratefully acknowledged. We thank Markus Otto, MD (University of Ulm) for helpful discussion.

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The contributing authors have no current or potential conflicts of interest.

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Authors and Affiliations

  1. Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany

    Heiko Braak & Kelly Del Tredici

  2. Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, The Sahlgrenska Academy at University of Gothenburg, Mölndal Campus, 431 80, Mölndal, Sweden

    Henrik Zetterberg & Kaj Blennow

  3. UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Henrik Zetterberg

Authors
  1. Heiko Braak
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  2. Henrik Zetterberg
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  4. Kaj Blennow
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Correspondence to Heiko Braak.

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Braak, H., Zetterberg, H., Del Tredici, K. et al. Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-β changes occur before increases of tau in cerebrospinal fluid. Acta Neuropathol 126, 631–641 (2013). https://doi.org/10.1007/s00401-013-1139-0

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  • DOI: https://doi.org/10.1007/s00401-013-1139-0

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