Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis
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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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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.”
From Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia (2013) · cites this paper as Small, 2008
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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)
- PMC
- PMC2692134
- 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
- bronze
- doi.org
- Licence
- 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
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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