Cited by 546Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis

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Small, Scott A., Duff, Karen·2008·Neuron

Abstract

Alzheimer's disease is characterized by abnormal elevation of Abeta peptide and abnormal hyperphosphorylation of the tau protein. The "amyloid hypothesis," which is based on molecular defects observed in autosomal-dominant early-onset Alzheimer's disease (EOAD), suggests a serial model of causality, whereby elevation of Abeta drives other disease features including tau hyperphosphorylation. Here, we review recent evidence from drug trials, genetic studies, and experimental work in animal models that suggests that an alternative model might exist in late-onset AD (LOAD), the complex and more common form of the disease. Specifically, we hypothesize a "dual pathway" model of causality, whereby Abeta and tau can be linked by separate mechanisms driven by a common upstream driver. This model may account for the results of recent drug trials and, if confirmed, may guide future drug development.

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Crossref · 10.1016/j.neuron.2008.11.007

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  • The possibility that neuronal injury biomarkers occur independently of Aβ would rather support hypotheses suggesting that tau pathology could occur independently from Aβ accumulation than the amyloid hypothesis.

    “This would rather support hypotheses suggesting that tau pathology could occur independently from Aβ accumulation (Small, 2008), than the amyloid hypothesis where tau-related neurodegeneration is supposed to appear downstream to Aβ.”

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Authors
Small, S. A., & Duff, K.
Affiliations
Columbia University (US)
Corresponding author
  • Small, Scott A.
  • Duff, Karen
Venue
Neuron
Publisher
Elsevier BV
Published
2008-11
Volume
60
Issue
4
Pages
534-542
ISSN
0896-6273 (ISSN-L)
OpenAlex
W1985871594
Cited by
546
References
111
Citations by year
2026: 12 · 2025: 22 · 2024: 23 · 2023: 20 · 2022: 21 · 2021: 36 · 2020: 29 · 2019: 35 · 2018: 36 · 2017: 20 · 2016: 35 · 2015: 34 · 2014: 34 · 2013: 26 · 2012: 35
FWCI
4.63
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG008702, P01AG007232, AG 07232, AG025161, R01AG025161, P50AG008702, P01AG017216, AG017216)
  • National Institute of Neurological Disorders and Stroke (P01NS048447, NS048447)
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, late-onset Alzheimer's disease, amyloid-beta, tau hyperphosphorylation, amyloid hypothesis, disease causality, drug trials, genetic research, animal models
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Models, Neurological, Phosphorylation, Amyloid beta-Peptides, tau Proteins, Genetic Predisposition to Disease, Apolipoprotein E4, Plaque, Amyloid

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