ORCID: https://orcid.org/0000-0003-3423-457X; Wagner, Fabian ORCID: https://orcid.org/0009-0009-7350-465X; Evangelista, Lisa ORCID: https://orcid.org/0009-0006-2396-4656; Rauchmann, Boris-Stephan ORCID: https://orcid.org/0000-0003-4547-6240; Dehsarvi, Amir ORCID: https://orcid.org/0000-0001-7116-9741; Steward, Anna ORCID: https://orcid.org/0000-0002-8438-3760; Dewenter, Anna ORCID: https://orcid.org/0000-0002-5636-196X; Biel, Davina ORCID: https://orcid.org/0000-0002-2597-1992; Zhu, Zeyu ORCID: https://orcid.org/0000-0003-0970-4832; Pescoller, Julia; Groß, Mattes ORCID: https://orcid.org/0009-0001-7729-2182; Perneczky, Robert ORCID: https://orcid.org/0000-0003-1981-7435; Malpetti, Maura ORCID: https://orcid.org/0000-0001-8923-9656; Ewers, Michael ORCID: https://orcid.org/0000-0001-5231-1714; Schöll, Michael ORCID: https://orcid.org/0000-0001-7800-1781; Dichgans, Martin ORCID: https://orcid.org/0000-0002-0654-387X; Höglinger, Günter U. ORCID: https://orcid.org/0000-0001-7587-6187; Brendel, Matthias ORCID: https://orcid.org/0000-0002-9247-2843; Jäkel, Sarah ORCID: https://orcid.org/0000-0002-9634-2472 und Franzmeier, Nicolai ORCID: https://orcid.org/0000-0001-9736-2283
(2025):
Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer’s disease.
In: Science Translational Medicine, Bd. 17, Nr. 782
Abstract
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.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin > Munich Cluster for Systems Neurology (SyNergy)
Medizin > Institut für Schlaganfall- und Demenzforschung (ISD) Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut Medizin > Klinikum der LMU München > Klinik und Poliklinik für Nuklearmedizin Medizin > Klinikum der LMU München > Klinik und Poliklink für Psychiatrie und Psychotherapie |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| ISSN: | 1946-6234 |
| Sprache: | Englisch |
| Dokumenten ID: | 124429 |
| Datum der Veröffentlichung auf Open Access LMU: | 23. Feb. 2025 06:59 |
| Letzte Änderungen: | 23. Feb. 2025 06:59 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
- Dokument bearbeiten
