The DOI matches its Crossref record; 75 of the 75 references it cites were found in a registry or an index.
Stages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years
Abstract
Two thousand three hundred and thirty two nonselected brains from 1- to 100-year-old individuals were examined using immunocytochemistry (AT8) and Gallyas silver staining for abnormal tau; immunocytochemistry (4G8) and Campbell-Switzer staining were used for the detection ofβ-amyloid. A total of 342 cases was negative in the Gallyas stain but when restaged for AT8 only 10 were immunonegative. Fifty-eight cases had subcortical tau predominantly in the locus coeruleus, but there was no abnormal cortical tau (subcortical Stages a-c). Cortical involvement (abnormal tau in neurites) was identified first in the transentorhinal region (Stage 1a, 38 cases). Transentorhinal pyramidal cells displayed pretangle material (Stage 1b, 236 cases). Pretangles gradually became argyrophilic neurofibrillary tangles (NFTs) that progressed in parallel with NFT Stages I to VI. Pretangles restricted to subcortical sites were seen chiefly at younger ages. Of the total cases, 1,031 (44.2%) had β-amyloid plaques. The first plaques occurred in the neocortex after the onset of tauopathy in the brainstem. Plaques generally developed in the 40s in 4% of all cases, culminating in their tenth decade (75%). β-amyloid plaques and NFTs were significantly correlated (p < 0.0001). These data suggest that tauopathy associated with sporadic Alzheimer disease may begin earlier than previously thought and possibly in the lower brainstem rather than in the transentorhinal region.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Up to 60% of CU individuals over age 80 years have AD neuropathologic changes at autopsy or by biomarkers [60,152,212–214].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [213]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“screening revealed low rates of Braak 1–2 NFT stages in all three groups (Table 2), consistent with literature-based norms [3].”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It should be noted that tau aggregation in the brain is associated with older age and is generally uncommon in healthy young adults (Braak et al., 2011; Crary et al., 2014).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Braak et al., 2011
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“It is expected that many persons die with brains that exhibit AD neuropathologic change in the preclinical phase of AD; indeed, data support the modeled expectations (44, 142).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [44]
The cited source says what the claim attributes to it.
In the citing paper
“Medial temporal and brainstem neurofibrillary changes were observed in our older TSC subjects, as expected, but at a rate comparable to that observed in the epilepsy and non-neurological control groups and age-based norms [3].”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [3]
In the citing paper
“In individuals with autosomal dominant mutations in genes coding for amyloid precursor protein (APP) or Presenilin 119 , alterations in Aβ generation that result in early deposition of plaque initiate the disease and patients invariably develop the full spectrum of tau pathology 120,121 .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [121]
In the citing paper
“NFTs first appear in layer II of the entorhinal cortex (EC) during AD onset.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [231]
In the citing paper
“NFTs subsequently appear in interconnected anatomical regions within the brain, including the hippocampus and neocortex during neurodegenerative progression [229–231].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [231]
In the citing paper
“Furthermore, it impairs adult hippocampal neurogenesis in mice and affects cortical thickness, brain activity, and mitochondrial function well before significant Aβ accumulation in the human brains [74–76].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [76]
In the citing paper
“Most of all, this binary threshold does not reflect the reality of amyloid β and tau pathology, which is continuous and present at a minimal extent in almost all people older than 70 years,17 with important discrepancies between pathology burden and clinical symptoms at intermediate extents (panel 2).”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [17]
In the citing paper
“For tau biomarkers, there is also a strong discrepancy between neuropathological identification (in post-mortem studies, the presence of tau Braak stages I–II is almost universal after age 70 years)17,19 and in-vivo measures of tau aggregates on PET (36% of individuals are tau positive after the age of 70 years23).”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [17]
In the citing paper
“The concordance of genetics and Aβ deposition is aligned with CPC studies that indicate that AβPs may be a temporally “upstream” feature of the neocortical disease, with the caveats that brainstem and medial temporal lobe pretangles and NFTs are seen in subjects without Aβ deposition in all age categories (33, 39, 44).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [44]
In the citing paper
“In contrast to NFTs, AβPs are extracellular (45, 46) and are found in a high proportion of all elderly persons but are not universal (44, 47, 48).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [44]
In the citing paper
“Recently, it has been reported that NFTs are also very common in certain brainstem nuclei in subjects without dementia (39-44).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [44]
In the citing paper
“Neurofibrillary pathology is observed in the human brain long before Aβ plaques develop (39, 44, 300).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [44]
In the citing paper
“Neuritic plaques seem to develop after diffuse AβPs and NFTs (44).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [44]
In the citing paper
“At 40 years, all individuals studied by Braak and Del Tredici (39) and Braak et al (44) exhibited at least initial neurofibrillary pathology in the brainstem (Fig. 5).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · cited 2×
“The first lesions were usually seen in the transentorhinal region (2).”
BackgroundSelf-citationThe Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Staging of brain pathology related to sporadic Parkinson’s disease
Braak, H., Tredici, K. D., Rüb, U., de Vos, R. A. I., Jansen Steur, E. N. H., & Braak, E. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00065-9 · Cited by 10,777
Self-citationHypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
Jack, C. R., Knopman, D. S., Jagust, W. J., Shaw, L. M., Aisen, P. S., Weiner, M. W., Petersen, R. C., & Trojanowski, J. Q. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70299-6 · Cited by 4,806
Aston-Jones, G., & Cohen, J. D. (2005) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.28.061604.135709 · Cited by 4,472
Phases of Aβ-deposition in the human brain and its relevance for the development of AD
Thal, D. R., Rüb, U., Orantes, M., & Braak, H. (2002) · Neurology · doi:10.1212/wnl.58.12.1791 · Cited by 3,490
Self-citationBraak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H., & Del Tredici, K. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0127-z · Cited by 3,172
Self-citationA Century of Alzheimer's Disease
Goedert, M., & Spillantini, M. G. (2006) · Science · doi:10.1126/science.1132814 · Cited by 2,153
The locus coeruleus and noradrenergic modulation of cognition
Sara, S. J. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2573 · Cited by 1,848
Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories
Braak, H., & Braak, E. (1997) · Neurobiology of Aging · doi:10.1016/s0197-4580(97)00056-0 · Cited by 1,656
Self-citation
Cited by
Sorted by citations
Items 1,001–1,010 of 1,010
[124I]IBETA: A New Aβ Plaque Positron Emission Tomography Imaging Agent for Alzheimer’s Disease
Nguyen, G. A. H., Liang, C., & Mukherjee, J. (2022) · Molecules · doi:10.3390/molecules27144552 · Cited by 20
Heneghan, A., Deng, F., Wells, K., Ritchie, K., Muniz-Terrera, G., Ritchie, C. W., Lawlor, B., & Naci, L. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-220267 · Cited by 18
Schwab, N., & Hazrati, L.-N. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-180373 · Cited by 18
Gal, J., Katsumata, Y., Zhu, H., Srinivasan, S., Chen, J., Johnson, L. A., Wang, W.-X., Golden, L. R., Wilcock, D. M., Jicha, G. A., et al. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.11.013 · Cited by 17
Tuberous sclerosis complex is associated with a novel human tauopathy
Hwang, J.-H. L., Perloff, O. S., Gaus, S. E., Benitez, C., Alquezar, C., Cosme, C. Q., Nana, A. L., Vatsavayai, S. C., Ramos, E. M., Geschwind, D. H., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-022-02521-5 · Cited by 15
“Medial temporal neurofibrillary tauopathy is a common finding in middle-aged adults, and screening revealed low rates of Braak 1–2 NFT stages in all three groups (Table 2), consistent with literature-based norms [3].”
ResultTherapeutic news in Alzheimer’s disease: Soon a disease-modifying therapy?
Villain, N. (2022) · Revue Neurologique · doi:10.1016/j.neurol.2022.02.456 · Cited by 14
Younes, K., Smith, V., Johns, E., Carlson, M. L., Winer, J., He, Z., Henderson, V. W., Greicius, M. D., Young, C. B., & Mormino, E. C. (2024) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2024.05.002 · Cited by 13
Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer’s Disease
Gomar, J. J., Conejero-Goldberg, C., Davies, P., Goldberg, T. E., & Initiative, F. T. A. D. N. (2016) · Journal of Alzheimer’s Disease · doi:10.3233/jad-150937 · Cited by 13
Kim, E.-J., Vatsavayai, S., & Seeley, W. W. (2016) · The Behavioral Neurology of Dementia · doi:10.1017/9781139924771.008 · Cited by 7
m6A-dependent circular RNA formation mediates tau-induced neurotoxicity
Atrian, F., Ramirez, P., De Mange, J., Marquez, M., Gonzalez, E. M., Minaya, M., Karch, C. M., & Frost, B. (2024) · doi:10.1101/2024.01.25.577211 · Cited by 7
Metadata
- Authors
- Braak, H., Thal, D. R., Ghebremedhin, E., & Del Tredici, K.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- Braak, Heiko
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-11
- Volume
- 70
- Issue
- 11
- Pages
- 960-969
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W1993023011
- Cited by
- 2,194
- References
- 75
- Citations by year
- 2026: 152 · 2025: 192 · 2024: 260 · 2023: 233 · 2022: 192 · 2021: 235 · 2020: 182 · 2019: 144 · 2018: 121 · 2017: 110 · 2016: 100 · 2015: 85 · 2014: 78 · 2013: 65 · 2012: 42
- FWCI
- 41.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer Forschung Initiative (10810)
- Deutsche Forschungsgemeinschaft (TH624 4–1)
- 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, pathological staging, tauopathy, neurofibrillary tangles, amyloid plaques, locus coeruleus, brainstem, sporadic Alzheimer's disease, AT8 antibody
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Neurons, Cohort Studies, Amyloid beta-Peptides, Silver Staining, Neurofibrillary Tangles, tau Proteins, Disease Progression, Statistics, Nonparametric, Young Adult
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
