Acta Neuropathologica

, Volume 126, Issue 5, pp 631–641 | Cite as

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

  • Heiko BraakEmail author
  • Henrik Zetterberg
  • Kelly Del Tredici
  • Kaj Blennow


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.


Abnormal tau protein Alzheimer’s disease Amyloid-β protein Cerebrospinal fluid Diffuse plaques Neurofibrillary tangles Pretangles Tau 



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.

Conflict of interest

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


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Heiko Braak
    • 1
    Email author
  • Henrik Zetterberg
    • 2
    • 3
  • Kelly Del Tredici
    • 1
  • Kaj Blennow
    • 2
  1. 1.Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical ResearchUniversity of UlmUlmGermany
  2. 2.Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska University HospitalThe Sahlgrenska Academy at University of GothenburgMölndalSweden
  3. 3.UCL Institute of NeurologyLondonUK

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