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Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease
Roemer-Cassiano SN, Wagner F, Evangelista L, Rauchmann BS, Dehsarvi A, Steward A, Dewenter A, Biel D, Zhu Z, Pescoller J, Gross M, Perneczky R, et al.. Science Translational Medicine, 2025-01-22
Topic: Amyloid, tau and blood-test diagnosis
In Alzheimer's disease (AD), amyloid-β (Aβ) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration and cognitive decline. However, the pathophysiological link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Aβ has been found to trigger neuronal hyperactivity and hyperconnectivity, and preclinical research has shown that tau spreads across connected neurons in an activity-dependent manner. Here, we hypothesized that neuronal hyperactivity and hypersynchronicity, resulting in functional connectivity increases, constitute a crucial mechanism by which Aβ facilitates the spreading of tau pathology. By combining Aβ positron emission tomography (PET), resting-state functional magnetic resonance imaging, and longitudinal tau-PET in 69 cognitively normal amyloid-negative controls and 140 amyloid-positive patients covering the AD spectrum, we confirmed that Aβ induces hyperconnectivity of temporal lobe tau epicenters to posterior brain regions that are vulnerable to tau accumulation in AD. This was replicated in an independent sample of 55 controls and 345 individuals with preclinical AD and low cortical tau-PET uptake, suggesting that the emergence of Aβ-related hyperconnectivity precedes neocortical tau spreading . Last, using longitudinal tau-PET and mediation analysis, we confirmed that these Aβ-related connectivity increases in tau epicenters to typical tau-vulnerable brain regions in AD mediated the effect of Aβ on faster tau accumulation, unveiling increased connectivity as a potential causal link between the two AD hallmark pathologies. Together, these findings suggest that Aβ promotes tau spreading by eliciting neuronal hyperconnectivity and that targeting Aβ-related neuronal hyperconnectivity may attenuate tau spreading in AD.
Key findings
- Aβ has been found to trigger neuronal hyperactivity and hyperconnectivity, and preclinical research has shown that tau spreads across connected neurons in an activity-dependent manner.
- This was replicated in an independent sample of 55 controls and 345 individuals with preclinical AD and low cortical tau-PET uptake, suggesting that the emergence of Aβ-related hyperconnectivity precedes neocortical tau spreading .
- Together, these findings suggest that Aβ promotes tau spreading by eliciting neuronal hyperconnectivity and that targeting Aβ-related neuronal hyperconnectivity may attenuate tau spreading in AD.
Why it matters
Combining amyloid PET, resting-state functional MRI and longitudinal tau-PET in controls and amyloid-positive patients, this study found that amyloid-beta induces hyperconnectivity of temporal lobe tau epicenters to vulnerable posterior brain regions, and that this precedes neocortical tau spreading. It identifies a mechanism by which amyloid-beta promotes tau spread, which may inform therapeutic efforts, but no treatment is tested.
Study details
- Study designcohort
- Participants609
- Evidence strengthModerate
How this study scored 68/100
Published in a peer-reviewed journal, and it is a cohort study following people over time. Scored zero for effect reported and randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 67 of the 98 points we could judge it on, which is 68 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Science Translational Medicine) |
| Journal's citation record | 3 / 4 | Science Translational Medicine: journal h-index 365 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 609 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 90 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 30.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 6 / 6 | Cited 49.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 4 other studies in this library |
| Still being cited | 3 / 4 | Cited 90 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Nicolai Franzmeier: h-index 49 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39841807) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 67 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 67 of the 98 points we could judge it on is 68 out of 100. |
| Total | 68 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1126/scitranslmed.adp2564
- PubMed: 39841807
- Original source →
- Free full text: discovery.ucl.ac.uk →
Full text: free to read — Unpaywall lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Roemer-Cassiano, S. N., Wagner, F., Evangelista, L., Rauchmann, B. S., Dehsarvi, A., Steward, A., et al. (2025). Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.adp2564
Vancouver
Roemer-Cassiano SN, Wagner F, Evangelista L, Rauchmann BS, Dehsarvi A, Steward A, et al. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease. Science Translational Medicine. 2025. doi:10.1126/scitranslmed.adp2564. PMID: 39841807.
BibTeX
@article{roemercassiano2025-39841807,
author = {Roemer-Cassiano, S. N. and Wagner, F. and Evangelista, L. and Rauchmann, B. S. and Dehsarvi, A. and Steward, A. and Dewenter, A. and Biel, D. and Zhu, Z. and Pescoller, J. and Gross, M. and Perneczky, R. and others},
title = {{Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease}},
journal = {Science Translational Medicine},
year = {2025},
doi = {10.1126/scitranslmed.adp2564},
pmid = {39841807},
url = {https://doi.org/10.1126/scitranslmed.adp2564}
}
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