Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry
Open accessAbstract
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 mum) 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 mum) 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.
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Accumulation of Aβ plaques and NFTs follows distinct regional progressions across brain regions as AD advances.
“Accumulation of Aβ plaques and NFTs follows distinct regional progressions across brain regions as AD advances.”
From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [14]
The staging-system section describes a predictable regional progression of neurofibrillary pathology, from transentorhinal and entorhinal regions to limbic and then neocortical areas. It does not describe a separate regional progression of Aβ plaques or compare that progression with NFTs. Its references to neuritic plaques occur in the context of tau-immunoreactive pathology, not an Aβ-plaque staging scheme. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe pTau/tau ratio pattern is consistent with the stereotypical hierarchical accumulation of NFTs along neural networks.
“consistent with the stereotypical hierarchical accumulation of NFTs along neural networks20,21”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [21]
The staging system section describes a predictable sequence of neurofibrillary lesions across six stages, supporting the claim of stereotypical, hierarchical accumulation. It does not establish that accumulation occurs along neural networks; it describes the anatomical distribution of lesions instead. The pTau/tau ratio is the citing authors’ framing, not a finding attributed to this source by the cited sentence. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAD cases were categorized into stage C of amyloid deposition and stage VI of neurofibrillary degeneration, following Braak's staging.
“They were categorized into the stage C of amyloid deposition and the stage VI of neurofibrillary degeneration, following the Braak's staging (13).”
From Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease (2017) · cites this paper as [13]
The staging system section defines six stages of AD-related neurofibrillary pathology, and its description of stage VI supports the cited basis for that classification. The passages do not describe a stage C of amyloid deposition or establish how the citing paper’s cases were categorized. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe primary visual cortex (V1) bears NFTs only in Braak NFT stage VI.
“by definition, the primary visual cortex (V1 region) bears NFTs only in Braak NFT stage VI20,21”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [21]
The five brain regions are hierarchically vulnerable to neurofibrillary degeneration in the order EC > ITG > PFC > V2 > V1.
“we rank ordered the five brain regions based on their known vulnerability to neurofibrillary degeneration20,21 (that is, EC > ITG > PFC > V2 > V1)”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [21]
The distinguishing feature between Braak NFT stages V and VI is not just the presence of NFTs in V1, motor and sensory cortical areas, but more severe neurofibrillary degeneration and atrophy throughout the cortical mantle.
“the distinguishing feature between Braak NFT stages V and VI is not just the presence of NFTs in the primary visual (V1), motor and sensory cortical areas, but more severe neurofibrillary degeneration21 and atrophy throughout the cortical mantle51”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [21]
Loss of neurons occurs predominantly in the cortex, the hippocampal formation, and the nucleus basalis of Meynert in AD.
“A further pathological determinant is loss of neurons, which occurs predominantly in the cortex, the hippocampal formation, and the nucleus basalis of Meynert [2, 3, 18, 22, 25].”
From Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice (2008) · cites this paper as [2]
Most brains from elderly human subjects show abnormalities that fall somewhere along particular continua of pathologic severity.
“We consider it to be an important clue that most brains from elderly human subjects show abnormalities that fall somewhere along particular continua of pathologic severity (60, 96-100).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [99]
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“As such, for the ROSMAP study, we had individuals with a Braak neurofibrillary tangle (NFT) score (Braak et al., 2006) greater than Wan et al.”
Method
- Authors
- Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H., & Del Tredici, K.
- Affiliations
- Goethe University Frankfurt (DE)
- Kuopio University Hospital (FI)
- Institut für Neuropathologie (DE)
- Corresponding author
- Braak, Heiko
- Venue
- Acta Neuropathologica
- Published
- 2006-08-12
- Volume
- 112
- Issue
- 4
- Pages
- 389-404
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3906709
- OpenAlex
- W2093650784
- Cited by
- 3,172
- References
- 101
- Citations by year
- 2026: 218 · 2025: 259 · 2024: 334 · 2023: 254 · 2022: 251 · 2021: 261 · 2020: 228 · 2019: 205 · 2018: 157 · 2017: 135 · 2016: 140 · 2015: 118 · 2014: 134 · 2013: 95 · 2012: 77
- FWCI
- 34.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Acta Neuropathologica (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission (LSHM-CT-2004-503039)
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, neurofibrillary pathology, disease staging, AT8 antibody, immunocytochemistry, paraffin sections, silver staining
- MeSH terms
- Alzheimer Disease, Humans, Immunohistochemistry, Amyloid beta-Peptides, Paraffin Embedding, Tissue Fixation, Neurofibrillary Tangles, tau Proteins, Disease Progression
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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