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Cited by 540Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease

Braak, Heiko, Del Tredici, Kelly·2015·Brain
DOI 10.1093/brain/awv236
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Abstract

Abnormal tau lesions (non-argyrophilic pretangle material, argyrophilic neuropil threads, neurofibrillary tangles) in select types of neurons are crucial for the pathogenesis of sporadic Alzheimer’s disease. Ongoing formation of these tau lesions persists into end-stage Alzheimer’s disease and is not subject to remission. The early pretangle disease phase is a focus of increasing interest because only abnormal forms of the microtubule-associated protein tau are involved at that point and, in contrast to late-stage disease when amyloid-β deposition is present, this phase is temporally closer to the prevailing conditions that induce the pathological process underlying Alzheimer’s disease. Extracellular and aggregated amyloid-β may only be produced under pathological conditions by nerve cells that contain abnormal tau. One potential trigger for tau protein hyperphosphorylation and conformational change in Alzheimer’s disease may be the presence of a non-endogenous pathogen. Subsequently, a predictable regional distribution pattern of the tau lesions develops in phylogenetically late-appearing and ontogenetically late-maturing neurons that are connected via their axons. It is hoped that hypotheses drawn from these considerations, as well as from recent tau dissemination models, from studies of variant tau conformers, and from tau imaging will encourage the development of new preventative and disease-modifying strategies. Neurofibrillary tangles containing abnormally phosphorylated tau protein accumulate in Alzheimer's disease. Braak and Del Tredici review the mechanisms and consequences of the earliest stages of tau lesion accumulation, prior to the emergence of cognitive impairment, and speculate on implications for disease prevention and modification.

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Cited by

Sorted by citations

Authors
Braak, H., & Del Tredici, K.
Affiliations
Universität Ulm (DE)
ORCID
Braak, Heiko
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2015-08-17
Volume
138
Issue
10
Pages
2814-2833
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awv236
OpenAlex
W1915842929
Cited by
540
References
27
Citations by year
2026: 49 · 2025: 52 · 2024: 70 · 2023: 57 · 2022: 40 · 2021: 57 · 2020: 59 · 2019: 51 · 2018: 38 · 2017: 31 · 2016: 33 · 2015: 3
FWCI
4.30
Type
journal article
Language
en
Open access
closed
Locations
  • Brain (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
Universität Ulm
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
sporadic Alzheimer's disease, tau pathology, neurofibrillary tangles, tau hyperphosphorylation, amyloid-beta, tau imaging, disease-modifying therapy, disease prevention, axonal connectivity
MeSH terms
Age Factors, Alzheimer Disease, Animals, Brain, Humans, Amyloid beta-Peptides, tau Proteins, Disease Progression

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