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@ARTICLE{RoemerCassiano:276160,
      author       = {Roemer-Cassiano, Sebastian N and Wagner, Fabian and
                      Evangelista, Lisa and Rauchmann, Boris-Stephan and Dehsarvi,
                      Amir and Steward, Anna and Dewenter, Anna and Biel, Davina
                      and Zhu, Zeyu and Pescoller, Julia and Gross, Mattes and
                      Perneczky, Robert and Malpetti, Maura and Ewers, Michael and
                      Schöll, Michael and Dichgans, Martin and Höglinger,
                      Günter U and Brendel, Matthias and Jäkel, Sarah and
                      Franzmeier, Nicolai},
      title        = {{A}myloid-associated hyperconnectivity drives tau spread
                      across connected brain regions in {A}lzheimer's disease.},
      journal      = {Science translational medicine},
      volume       = {17},
      number       = {782},
      issn         = {1946-6234},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DZNE-2025-00232},
      pages        = {eadp2564},
      year         = {2025},
      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.},
      keywords     = {Humans / Alzheimer Disease: metabolism / Alzheimer Disease:
                      pathology / Alzheimer Disease: diagnostic imaging / tau
                      Proteins: metabolism / Brain: metabolism / Brain: diagnostic
                      imaging / Brain: pathology / Aged / Amyloid beta-Peptides:
                      metabolism / Positron-Emission Tomography / Male / Female /
                      Magnetic Resonance Imaging / Middle Aged / Case-Control
                      Studies / Aged, 80 and over / tau Proteins (NLM Chemicals) /
                      Amyloid beta-Peptides (NLM Chemicals)},
      cin          = {AG Dichgans / Clinical Research (Munich)},
      ddc          = {500},
      cid          = {I:(DE-2719)5000022 / I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39841807},
      doi          = {10.1126/scitranslmed.adp2564},
      url          = {https://pub.dzne.de/record/276160},
}