Synergy between amyloid-β and tau in Alzheimer’s disease
Open accessAbstract
Patients with Alzheimer's disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this 'triggering' function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ-tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Most, if not all, studies have examined the synergy between Aβ and tau using the tauopathy-associated P301L mutant tau.
“Most, if not all, of these studies have examined the synergy between Aβ and tau using the tauopathy-associated P301L mutant tau (9).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [9]
The “Mechanistic lessons from AD models” section describes several Aβ–tau studies using P301L-mutant tau mice. It also describes a study using wild-type tau, and the section on neural-system consequences reports further wild-type-tau studies. The review therefore supports P301L as one model used, but not the claim that most, if not all, studies used it; page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAβ production leads to neuronal hyperactivity while mutant tau expression leads to silencing.
“This study showed that Aβ production leads to neuronal hyperactivity while mutant tau expression leads to silencing (9).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [9]
The section “Neural system functional consequences of Aβ–tau interactions” reports Aβ-related neuronal hyperexcitability and reduced activity in tau-expressing models. It describes reduced firing and suppression, rather than complete neuronal silencing, and identifies these findings as results of studies reviewed by this paper—not an original experiment in this paper. Page numbers were not available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredGrowing evidence indicates a critical interplay between Aβ and tau pathologies that drives disease progression, potentially through synapses and glial activation.
“A growing body of evidence highlights the critical interplay between these pathologies, potentially through synapses and glial activation, that drives disease progression.”
From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [4]
Hyperphosphorylated forms of tau in neurons is a major hallmark of AD.
“Hyperphosphorylated forms of the microtubule-associated protein tau in neurons is a major hallmark of AD [2, 3].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [2]
A 7-year longitudinal study of 60 clinically normal elderly found that increases in tau PET signal were significantly associated with cognitive decline; increases in amyloid PET were associated with increases in tau PET signal but not directly with cognitive decline.
“A 7-year longitudinal study was conducted in which 60 clinically normal elderly participants received repeated tau and amyloid PET scans and cognitive assessments 132 .This analysis revealed that increases in tau PET signal were significantly associated with cognitive decline, and while increases in amyloid PET were associated with increases in tau PET signal, it was not significantly directly ass”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [132]
The amyloid hypothesis posits that Aβ, most likely in its soluble oligomeric form, initiates a pathophysiological cascade leading to hyperphosphorylation and misfolding of tau.
“The most popular model is the “amyloid hypothesis”, which posits that Aβ, most likely in its soluble oligomeric form, initiates a pathophysiological cascade which leads to the hyperphosphorylation and misfolding of tau 139 .”
From Mental health care for older adults: recent advances and new directions in clinical practice and research (2022) · cites this paper as [139]
It seems likely that both amyloid and tau pathologies are important and have a synergistic effect in Alzheimer's disease.
“The complex Aβ‐tau interactions are incompletely understood, and it seems likely that both pathologies are important and have a synergistic effect 139 .”
From Mental health care for older adults: recent advances and new directions in clinical practice and research (2022) · cites this paper as [139]
Tau-induced suppression of neural networks can be relieved by turning off transgene expression, with restoration time consistent with soluble tau half-life, not fibrillar tau.
“Tau-induced suppression of neural networks can be relieved by turning off expression of the transgene, leading to rapid restoration of function in a time frame consistent with the half-life of soluble tau protein, not fibrillar tau.”
From All the Tau We Cannot See (2023) · cites this paper as [23]
Calcium imaging reveals suppressed network activity in presence of tau overexpression independent of fibril formation.
“In another example of this same principle, calcium imaging using multiphoton microscopy reveals suppressed network activity in the presence of tau overexpression (in this case either wild-type tau or P301L tau), independent of fibril formation (23, 24).”
From All the Tau We Cannot See (2023) · cites this paper as [23]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 153 · Cited by 1,242
- Authors
- Busche, M. A., & Hyman, B. T.
- Affiliations
- UK Dementia Research Institute (GB)
- Harvard University (US)
- Corresponding author
- Busche, Marc Aurel
- Venue
- Nature Neuroscience
- Published
- 2020-08-10
- Volume
- 23
- Issue
- 10
- Pages
- 1183-1193
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC11831977
- OpenAlex
- W3048109944
- Cited by
- 1,242
- References
- 153
- Citations by year
- 2026: 192 · 2025: 246 · 2024: 237 · 2023: 200 · 2022: 200 · 2021: 150 · 2020: 16 · 2013: 1
- FWCI
- 18.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- RCUK | Medical Research Council (MR/S017003/1, UKDRI-1010)
- BrightFocus Foundation (A2019112S)
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (P30AG062421)
- JPB Foundation
- Tau Consortium
- 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, amyloid-beta, tau protein, neurofibrillary tangles, amyloid plaques, pathogenesis, neurodegeneration, anti-tau therapy, disease-modifying therapy
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Neurons, Amyloid beta-Peptides, tau Proteins, 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 ›
Are you an author, or do you see a problem with this page? Request a review
