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The pathological process underlying Alzheimer’s disease in individuals under thirty
Abstract
Brains of 42 individuals between the ages of 4 and 29 were examined with antibodies (AT8, 4G8) and silver stains for the presence of intraneuronal and extracellular protein aggregates associated with Alzheimer's disease. Thirty-eight of 42 (38/42) cases displayed abnormally phosphorylated tau protein (pretangle material) in nerve cells or in portions of their cellular processes, and 41/42 individuals showed no extracellular amyloid-β protein deposition or neuritic plaques-an individual with Down syndrome was the only exception. In 16/42 cases abnormal tau was found in the transentorhinal region, and in 3/42 cases this site was Gallyas-positive for isolated NFTs (NFT stage I). Of 26 cases that lacked abnormal tau in the transentorhinal region, 4 did not show pretangle material at subcortical sites. The remaining 22 of these same 26 cases, however, had subcortical lesions confined to non-thalamic nuclei with diffuse projections to the cerebral cortex, and, remarkably, in 19/22 individuals the pretangle material was confined to the noradrenergic coeruleus/subcoeruleus complex. Assuming the pretangle alterations are not transient and do not regress, these findings may indicate that the Alzheimer's disease-related pathological process leading to neurofibrillary tangle formation does not begin in the cerebral cortex but, rather, in select subcortical nuclei, and it may start quite early, i.e., before puberty or in early young adulthood.
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“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 [39]
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 [39]
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 [39]
In the citing paper
“Although some studies have interpreted phosphorylated tau abnormalities in the locus coeruleus to be an early stage of AD pathology [15], young control subjects were not screened for a history of exposure to mTBI despite the fact that mTBI is common among young individuals and that 17 % of the control subjects died from acute trauma or accidental death.”
From The neuropathology of sport (2014) · cites this paper as [15]
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“The focal collections of perivascular NFTs in the depths of the cortical sulci in CTE [65, 66, 126–128] differ substantially from PHF-tau pathology of the Alzheimer type reported in some cognitively normal young adults [15], opiate abusers [4], and non-demented elderly subjects such as those in the Framingham Heart Study [6] or Honolulu Asian Aging Study [67, 194].”
From The neuropathology of sport (2014) · cites this paper as [15]
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Metadata
- Authors
- Braak, H., & Del Tredici, K.
- Affiliations
- Universität Ulm (DE)
- Corresponding author
- Braak, Heiko
- ORCID
- Braak, Heiko
- Venue
- Acta Neuropathologica
- Published
- 2010-12-15
- Volume
- 121
- Issue
- 2
- Pages
- 171-181
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2081533023
- Cited by
- 812
- References
- 103
- Citations by year
- 2026: 42 · 2025: 43 · 2024: 58 · 2023: 39 · 2022: 55 · 2021: 74 · 2020: 61 · 2019: 52 · 2018: 51 · 2017: 41 · 2016: 57 · 2015: 52 · 2014: 55 · 2013: 49 · 2012: 45
- FWCI
- 27.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (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, young adults, tau phosphorylation, neurofibrillary tangles, amyloid-beta, neuritic plaques, subcortical nuclei, AT8 antibody, Down syndrome
- MeSH terms
- Adolescent, Adult, Alzheimer Disease, Brain, Child, Child, Preschool, DNA-Binding Proteins, Female, Humans, Male, Neurons, Phosphorylation, Retrospective Studies, Cohort Studies, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Ubiquitin, Young Adult
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