Methods Report

Acta Neuropathologica

, Volume 112, Issue 4, pp 389-404

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry

  • Heiko BraakAffiliated withInstitute for Clinical Neuroanatomy, J.W. Goethe University Clinic Email author 
  • , Irina AlafuzoffAffiliated withInstitute of Clinical Medicine, Pathology, Kuopio University and University Hospital
  • , Thomas ArzbergerAffiliated withInstitute of Neuropathology, Ludwig Maximilians University
  • , Hans KretzschmarAffiliated withInstitute of Neuropathology, Ludwig Maximilians University
  • , Kelly Del TrediciAffiliated withInstitute for Clinical Neuroanatomy, J.W. Goethe University ClinicClinic for Psychiatry and Neurology Winnenden


Assessment of Alzheimer’s disease (AD)-related neurofibrillary pathology requires a procedure that permits a sufficient differentiation between initial, intermediate, and late stages. The gradual deposition of a hyperphosphorylated tau protein within select neuronal types in specific nuclei or areas is central to the disease process. The staging of AD-related neurofibrillary pathology originally described in 1991 was performed on unconventionally thick sections (100 μm) using a modern silver technique and reflected the progress of the disease process based chiefly on the topographic expansion of the lesions. To better meet the demands of routine laboratories this procedure is revised here by adapting tissue selection and processing to the needs of paraffin-embedded sections (5–15 μm) and by introducing a robust immunoreaction (AT8) for hyperphosphorylated tau protein that can be processed on an automated basis. It is anticipated that this revised methodological protocol will enable a more uniform application of the staging procedure.


Alzheimer’s disease Neurofibrillary changes Immunocytochemistry Hyperphosphorylated tau protein Neuropathologic staging Pretangles