The pathological process underlying Alzheimer’s disease in individuals under thirty

Braak, Heiko; Del Tredici, Kelly

doi:10.1007/s00401-010-0789-4

Cited by 813Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The pathological process underlying Alzheimer’s disease in individuals under thirty

Braak, Heiko, Del Tredici, Kelly·2011·Acta Neuropathologica

DOI 10.1007/s00401-010-0789-4

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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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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 [39]
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 [39]
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 [39]
Young control subjects in studies interpreting locus coeruleus phosphorylated tau abnormalities as early AD pathology were not screened for a history of exposure to mTBI, despite mTBI being common among young individuals and 17% of control subjects dying from acute trauma or accidental death.
“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]
Focal collections of perivascular NFTs in the depths of cortical sulci in CTE differ substantially from PHF-tau pathology of the Alzheimer type reported in cognitively normal young adults, opiate abusers, and non-demented elderly subjects.
“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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“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 brain-stem (Fig.”
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“In the earliest stages of AD (Braak stage I-II), NFTs are restricted to the entorhinal cortex (Braak and Del Tredici, 2011; Braak et al., 2011).”
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Amyloid-Beta and Phosphorylated Tau Accumulations Cause Abnormalities at Synapses of Alzheimer’s disease Neurons
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“In the brain, neurofibrillary tangles (B) occur first in the locus coeruleus and transentorhinal area and then spread to the amygdala and interconnected neocortical brain regions.(8,24) The relatively stereotyped patterns of expansion suggest the involvement of neuronal transport mechanisms in the spread of proteopath…”
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Tau and tauopathies
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Small Misfolded Tau Species Are Internalized via Bulk Endocytosis and Anterogradely and Retrogradely Transported in Neurons
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Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress
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Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel
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Authors: Braak, H., & Del Tredici, K.
Affiliations: Universität Ulm (DE)
Corresponding author: Braak, Heiko
ORCID: Braak, Heiko
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2010-12-15
Volume: 121
Issue: 2
Pages: 171-181
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-010-0789-4
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: 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, 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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The pathological process underlying Alzheimer’s disease in individuals under thirty

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