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.
“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]
The Abstract reports AD-related plaques in autopsy cases and says their prevalence reached 75% in the tenth decade. The Study Cohort describes nonselected autopsy cases, not a cognitively unimpaired (CU) group; the paper does not establish a 60% rate for CU people over 80 or report biomarker-based prevalence. (LLM, conf=0.86)
Experimental — accuracy not yet measuredScreening revealed low rates of Braak 1-2 NFT stages in all three groups, consistent with literature-based norms.
“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]
The section on neurofibrillary stages reports 589 Stage I and 497 Stage II cases among 2,332, providing literature-based frequencies for comparison. It does not establish that rates in the citing study’s three groups were low or consistent with those frequencies; those groups are not examined in this paper. (LLM, conf=0.82)
Experimental — accuracy not yet measuredTau aggregation in the brain is associated with older age and is generally uncommon in healthy young adults.
“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
The Intraneuronal Gallyas-Positive Abnormal tau Protein section reports that late neurofibrillary-tangle stages increased with age, supporting an age association for advanced pathology. But the Discussion reports abnormal tau in younger individuals and explicitly says the underlying process is not age-dependent; the paper does not establish that tau aggregation is generally uncommon in healthy young adults. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMedial temporal and brainstem neurofibrillary changes were observed in older TSC subjects at a rate comparable to the epilepsy and non-neurological control groups and age-based norms.
“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 individuals with autosomal dominant mutations in APP or Presenilin, altered Aβ generation causing early plaque deposition initiates the disease, and patients invariably develop the full spectrum of tau pathology.
“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]
NFTs first appear in layer II of the entorhinal cortex (EC) during AD onset.
“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]
NFTs subsequently appear in interconnected anatomical regions within the brain, including the hippocampus and neocortex during neurodegenerative progression.
“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]
ApoE4 impairs adult hippocampal neurogenesis in mice and affects cortical thickness, brain activity, and mitochondrial function well before significant amyloid-β accumulation in human brains.
“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]
The 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, with important discrepancies between pathology burden and clinical symptoms at intermediate extents.
“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]
For tau biomarkers, there is a strong discrepancy between neuropathological identification (tau Braak stages I-II almost universal after age 70) and in-vivo measures of tau aggregates on PET (36% of individuals are tau positive after age 70).
“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]
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.
“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]
AβPs are extracellular and are found in a high proportion of all elderly persons but are not universal.
“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]
NFTs are also very common in certain brainstem nuclei in subjects without dementia.
“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]
It is expected that many persons die with brains that exhibit AD neuropathologic change in the preclinical phase of AD; data support the modeled expectations.
“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]
Neurofibrillary pathology is observed in the human brain long before Aβ plaques develop.
“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]
Neuritic plaques seem to develop after diffuse AβPs and NFTs.
“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]
At 40 years, all individuals studied by Braak and Del Tredici and Braak et al exhibited at least initial neurofibrillary pathology in the brainstem.
“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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- 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
- 11
- 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
- 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, 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 ›
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