Spreading of Tau Pathology in Sporadic Alzheimer’s Disease Along Cortico-cortical Top-Down Connections
Open accessAbstract
By using AT8-immunocytochemistry that visualizes hyperphosphorylated tau protein, we examined neurofibrillary changes related to sporadic Alzheimer's disease (AD) in N = 40 individuals at neurofibrillary tangle (NFT) stages I-IV. We report the presence of abnormal tau changes within solitary pyramidal neurons in layers III and V of the neocortex. These pyramidal cells showed pathology in different cell compartments (dendritic, somatic, axonal) that appeared to occur sequentially: Tau pathology was seen in distal segments of the basal dendrites, then in proximal dendrites, the soma, and, finally, in the axon of affected neurons. These findings are remarkable in that they point to the existence of neurofibrillary changes in regions routinely associated with later NFT stages. In addition, they lend support to the idea that it may be the axons of cortico-cortical top-down neurons in neocortical fields involved in AD that carry and spread abnormal tau seeds in a focused manner (transsynaptically) into the distal dendritic segments of nerve cells following directly in the neuronal chain, thereby sustaining further tau-seeded templating.
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Toxic species of aggregated tau affect pyramidal-cell dendritic complexity even before axonal aggregation.
“Toxic species of aggregated tau affect pyramidal‐cell dendritic complexity 10 , 16 even before axonal aggregation. 10”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [10]
The Results (Group 1 and Fig. 2; page unavailable) describe bent, thickened pyramidal-cell dendrites containing abnormal tau. Figure 5 proposes that dendritic tau aggregates appear before axonal tau involvement. The paper does not establish that toxic tau species cause a change in dendritic complexity; it reports morphological observations and a proposed sequence. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPyramidal cells are directly affected by extracellular amyloid beta plaques and intraneuronal tau tangles.
“Pyramidal cells are directly affected by the molecular hallmarks of AD: extracellular amyloid beta (Aβ) plaques 9 and intraneuronal tau tangles. 10”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [10]
Tau aggregates develop in pyramidal cells and can spread between pyramidal cells.
“Tau aggregates develop in pyramidal cells and can spread between pyramidal cells. 10”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [10]
The lack of significant effect on primary auditory cortices is in accord with the classical progression of pathology over Braak stages with very late involvement of primary sensory cortices in disease staging.
“in accord with the classical progression of pathology over Braak stages with very late involvement of primary sensory cortices in disease staging. 10”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [10]
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- Braak, H., & Del Tredici, K.
- Affiliations
- Universität Ulm (DE)
- Clinical Neuroanatomy Section/Department of Neurology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, Ulm, Germany
- Corresponding author
- Braak, Heiko
- ORCID
- Braak, Heiko
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-06-30
- Volume
- 28
- Issue
- 9
- Pages
- 3372-3384
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC6095209
- OpenAlex
- W2810078757
- Cited by
- 148
- References
- 87
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 25 · 2023: 17 · 2022: 23 · 2021: 25 · 2020: 20 · 2019: 11 · 2018: 2
- FWCI
- 9.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cerebral Cortex (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Hans and Ilse Breuer Foundation
- 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
- tau pathology, sporadic Alzheimer's disease, neurofibrillary tangles, hyperphosphorylated tau, pyramidal neurons, neocortex, tau seeding
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Middle Aged, Neurofibrillary Tangles, tau Proteins, Pyramidal Cells
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