Cited by 838Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Staging of Alzheimer-Related Cortical Destruction

Braak, Heiko, Braak, Eva, Bohl, Jürgen·2008·European Neurology

DOI 10.1159/000116984

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Abstract

The gradual intraneuronal accumulation of an insoluble fibrous material which partly consists of abnormally phosphorylated tau protein (neurofibrillary change) represents an important neuropathological hallmark of Alzheimer’s disease. Neurofibrillary tangles and neuropil threads formed from this material develop in only a few types of cortical pyramidal cells. The first changes are seen in the entorhinal cortex. The destructive process then spreads into the hippocampal formation and eventually encroaches upon the isocortex. This sequence of events permits the distinction of six stages with a progressive increase in the severity of cortical destruction. The entorhinal region serves as an important interface between the isocortex and hippocampus. This interface function is markedly impaired due to the early deterioration of the entorhinal cortex. Severe entorhinal involvement is considered to represent the morphological counterpart of clinically incipient Alzheimer’s disease. Similar changes are found in mentally impaired individuals suffering from Parkinson’s disease or progressive supranuclear palsy.

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Background
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“The hippocampus plays an important role in processing olfactory information, including recall and identification of odors,(37) and histopathological studies in AD have shown that neurofibrillary tangles (hallmark of AD) develop initially and remain the most severe in the entorhinal cortex and hippocampus.(38) Neurodeg…”
Background
Die leichte kognitive Beeinträchtigung
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Biliverdin Reductase-A correlates with inducible nitric oxide synthasein in atorvastatin treated aged canine brain.
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“Alzheimer’s disease neuropathology is observed in the hippocampus and underlying cortex, as well as in neocortex but with the cerebellum remaining relatively spared until late in the disease [2-3] .”
Background
Effect of linearization correction on statistical parametric mapping (SPM): A99mTc-HMPAO brain perfusion SPECT study in mild Alzheimer’s disease
Ansar, A. B., Osaki, Y., Kazui, H., Oku, N., Takasawa, M., Kimura, Y., Begum, N. N., Ikejiri, Y., Takeda, M., & Hatazawa, J. (2006) · Annals of Nuclear Medicine · doi:10.1007/bf03026814 · Cited by 11
BIN1 Genetic Risk Factor for Alzheimer is Sufficient to Induce Early Structural Tract Alterations in Entorhinal-Hippocampal Area and Memory-Related Hippocampal Multi-Scale Impairments
Daudin, R., Marechal, D., Golgolab, R., Wang, Q., Abe, Y., Tsurugizawa, T., Bourg, N., Sartori, M., Loe-Mie, Y., Lipecka, J., et al. (2018) · doi:10.1101/437228 · Cited by 14
Alzheimer’s disease risk gene CD2AP is a dose-sensitive determinant of synaptic structure and plasticity
Pavešković, M., De-Paula, R. B., Ojelade, S. A., Tantry, E. K., Kochukov, M. Y., Bao, S., Veeraragavan, S., Garza, A. R., Srivastava, S., Song, S., et al. (2024) · Human Molecular Genetics · doi:10.1093/hmg/ddae115 · Cited by 11
“4A), given its vulnerability in early AD [1, 39] as well as the strong Cd2ap expression detected in this region (Fig.”
The neuropathology of HIV
Gelman, B. B. (2007) · Handbook of clinical neurology · doi:10.1016/s0072-9752(07)85018-4 · Cited by 10
Diagnostic utility of sound naming in early Alzheimer’s disease
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“Neurofi brillary tangles (NFT) and tau protein deposits develop fi rst in the limbic structures and spread to the neighboring temporal cortex as the disease worsens (Braak et al., 1993 ).”
Background
Performance on a 1-week delayed recall task is associated with medial temporal lobe structures in neurologically normal older adults
Saloner, R., Casaletto, K. B., Marx, G. A., Dutt, S., Bussche, A. B. V., You, M. Y., Fox, E. P., Stiver, J., & Kramer, J. H. (2017) · The Clinical Neuropsychologist · doi:10.1080/13854046.2017.1370134 · Cited by 14
Business Information Architecture for Big Data and Internet of Things
Sassi, M. S. H., Fourati, L. C., & Ghozzi, F. (2019) · doi:10.1109/iwcmc.2019.8766747 · Cited by 10
“Alzheimer [34] is the disease which destroys the memory of a person and other important mental function.”
Background
Neuroimaging in Dementia
Risacher, S. L. (2024) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001509 · Cited by 11
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Armstrong, R. A., & Cairns, N. J. (2010) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2010.01071.x · Cited by 10
“Apo E genotype of the AD cases was either 3/4 or 4/4 and the cases represented Braak stages IV, V, or VI [22].”
Background
Subject-performed tasks improve associative learning in amnestic mild cognitive impairment
Karantzoulis, S., Rich, J. B., & Mangels, J. A. (2006) · Journal of the International Neuropsychological Society · doi:10.1017/s1355617706060632 · Cited by 10
“Susceptibility to semantic interference has also been related to entorhinal cortex and hippocampal damage (Hasslemo & Wyble, 1997; Peinado-Manzano, 1994), which have been implicated in the pathology of aMCI (Jack et al., 1999) and early AD ( Braak et al., 1993 ).”
Background
Structural Magnetic Resonance Imaging Markers of Alzheimer’s Disease and Its Retranslation to Rodent Models
Kincses, Z. T., Király, A., Veréb, D., & Vécsei, L. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-143195 · Cited by 10
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Aberrant interactions between amyloid-beta and alpha5 laminins as possible driver of neuronal disfunction in Alzheimer’s disease
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The Usage of Histamine Type 1 Receptor Antagonist and Risk of Dementia in the Elderly: A Nationwide Cohort Study
Yang, C.-C., Chien, W., Chung, C., Lai, C., & Tzeng, N. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.811494 · Cited by 9
Amyloid pathology related to aberrant structure-function coupling of brain networks in Alzheimer’s disease: insights from [18F]-florbetapir PET imaging
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“Aβ deposition is recognized as a hallmark of AD progres - sion [1, 3] and has been linked to disruptions in both structural and functional connectivity, particularly within the DMN [45 ].”
A 512-Ch Dual-Mode Microchip for Simultaneous Measurements of Electrophysiological and Neurochemical Activities
Mulberry, G., White, K. A., Crocker, M. A., & Kim, B. N. (2023) · Biosensors · doi:10.3390/bios13050502 · Cited by 12
Infusion of human embryonic kidney cell line conditioned medium reverses kainic acid induced hippocampal damage in mice
Dhanushkodi, A., Venugopal, C., Bevinahal, P. K. K., Rai, K. S., Trichur, R. R., Talakad, S. N., & Bhonde, R. R. (2014) · Cytotherapy · doi:10.1016/j.jcyt.2014.07.001 · Cited by 8
Facilitation of memory impairment and cholinergic disturbance in a mouse model of Alzheimer's disease by mild ischemic burden
Watanabe, T., Takasaki, K., Yamagata, N., Fujiwara, M., & Iwasaki, K. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2012.12.041 · Cited by 9
Dynamic SAP 102 expression in the hippocampal subregions of rats and APP / PS 1 mice of various ages
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“Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by gradual memory loss and cognitive impairments, and the hippocampus is one of the first regions in the brain to suffer damage in AD (Braak & Braak, 1991; Braak et al. 1993; Greene & Killiany, 2012).”
Background
Volumetric GWAS of medial temporal lobe structures identifies an ERC1 locus using ADNI high-resolution T2-weighted MRI data
Cong, S., Yao, X., Huang, Z., Risacher, S. L., Nho, K. T., Saykin, A. J., & Shen, L. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.07.005 · Cited by 9
Immunohistoblot analysis on whole human hemispheres from normal and Alzheimer diseased brains
Beliczai, Z., Várszegi, S., Gulyás, B. Z., Halldin, C., Kása, P., & Gulya, K. (2008) · Neurochemistry International · doi:10.1016/j.neuint.2008.09.002 · Cited by 9
“The AD brains were obtained from patients with a clinical diagnosis of AD (McKhann et al., 1984), and the post-mortem neurohistological examinations on the AD brains justified the clinical diagnosis (Braak et al., 1993; Braak and Braak, 1997a,b; McKhann et al., 1984).”
Density and cross-sectional areas of axons in the olfactory tract in control subjects and Alzheimer’s disease: an image analysis study
Armstrong, R. A., Syed, A., & Smith, C. U. M. (2008) · Neurological Sciences · doi:10.1007/s10072-008-0854-0 · Cited by 9
“AD cases also had extensive NFT in hippocampal and cortical regions conforming to Braak stages IV to VI [13] (Table 1).”
Method
Quantization and analysis of hippocampal morphometric changes due to dementia of Alzheimer type using metric distances based on large deformation diffeomorphic metric mapping
Ceyhan, E., Beg, M. F., Ceritoglu, C., Wang, L., Morris, J. C., Csernansky, J. G., Miller, M. I., & Ratnanather, J. T. (2011) · Computerized Medical Imaging and Graphics · doi:10.1016/j.compmedimag.2011.01.005 · Cited by 9
The Usefulness of Biological and Neuroimaging Markers for the Diagnosis of Early‐Onset Alzheimer′s Disease
Padovani, A., Gilberti, N., & Borroni, B. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/296374 · Cited by 11
“From pathological and MRI studies, the hippocampus is known to be severely affected in established AD [47, 48].”
Background
Tau protein is differentially phosphorylated in young‐ and old‐aged rats with experimentally induced hyperthyroidism
Tan, B., Babür, E., Toy, N., Türker, B. G., Dursun, N., & Süer, C. (2022) · International Journal of Developmental Neuroscience · doi:10.1002/jdn.10220 · Cited by 8
“It has also been reported that NFT increases spontaneously in the aged brain (Braak et al., 1993).”
Background
Free-water: A promising structural biomarker for cognitive decline in aging and mild cognitive impairment
Sathe, A., Yang, Y., Schilling, K. G., Shashikumar, N., Moore, E. E., Dumitrescu, L. C., Pechman, K. R., Landman, B. A., Gifford, K. A., Hohman, T. J., et al. (2024) · Imaging Neuroscience · doi:10.1162/imag_a_00293 · Cited by 10
“The neuropathology-driven gray matter atrophy typically starts in the medial temporal lobe structures (e.g., ento-rhinal cortex, hippocampus) and then spreads to other regions of the brain ( Braak et al., 2008; Coup é et al., 2019).”
Background
Oxindole Derivatives as Multi‐Target Agents for Alzheimer's Disease: A Promising Therapeutic Strategy
Jhagta, C., & Singh, M. (2025) · ChemistrySelect · doi:10.1002/slct.202500743 · Cited by 8
Rare variants in the endocytic pathway are associated with Alzheimer’s disease, its related phenotypes, and functional consequences
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Adult Neurogenesis, Context Encoding, and Pattern Separation: A Pathway for Treating Overgeneralization
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Alzheimer’s Disease Biomarkers Have Distinct Associations with Specific Hippocampal Subfield Volumes
Müller‐Ehrenberg, L., Initiative, A. D. N., Riphagen, J. M., Verhey, F. R. J., Sack, A. T., & Jacobs, H. I. L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180676 · Cited by 9

Authors: Braak, H., Braak, E., & Bohl, J.
Affiliations: Goethe University Frankfurt (DE)
ORCID: Braak, Heiko
Venue: European Neurology
Publisher: S. Karger AG
Published: 2008-02-12
Volume: 33
Issue: 6
Pages: 403-408
ISSN: 0014-3022 (ISSN-L)
1421-9913
DOI: 10.1159/000116984
OpenAlex: W2095422335
Cited by: 836
References: 0
Citations by year: 2026: 15 · 2025: 27 · 2024: 29 · 2023: 34 · 2022: 38 · 2021: 32 · 2020: 35 · 2019: 33 · 2018: 30 · 2017: 40 · 2016: 35 · 2015: 47 · 2014: 36 · 2013: 39 · 2012: 35
FWCI: 29.38
Type: journal article
Language: en
Open access: closed
Licence: karger.com/pages/terms-and-conditions (vor)
karger.com/pages/terms-and-conditions (tdm)
Locations: European Neurology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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, cortical destruction, neurofibrillary tangles, tau protein, neuropil threads, entorhinal cortex, hippocampal formation, neocortex, disease staging, cortical pyramidal neurons, Parkinson's disease, progressive supranuclear palsy, neuropathology
MeSH terms: Aged, Alzheimer Disease, Brain Mapping, Cerebral Cortex, Dementia, Diagnosis, Differential, Hippocampus, Humans, Limbic System, Parkinson Disease, Supranuclear Palsy, Progressive, Neurites, Neurofibrillary Tangles

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Staging of Alzheimer-Related Cortical Destruction

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