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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.
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“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.
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“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.
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“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
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“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]
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“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]
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“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]
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“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]
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“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]
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“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]
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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
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