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@INPROCEEDINGS{RoemerCassiano:283063,
      author       = {Roemer-Cassiano, Sebastian and Zhang, Shaoshi and
                      Evangelista, Lisa and Dehsarvi, Amir and Klonowksi, Madleen
                      and Frontzkowski, Lukas and Rauchmann, Boris-Stephan and
                      Steward, Anna and Dewenter, Anna and Biel, Davina and Zhu,
                      Zeyu and Hirsch, Fabian and Pescoller, Julia and Perneczky,
                      Robert and Malpetti, Maura and Palleis, Carla and Gnoerich,
                      Johannes and Schöll, Michael and Dichgans, Martin and
                      Jäkel, Sarah and Höglinger, Günter U and Brendel,
                      Matthias and Yeo, Thomas and Franzmeier, Nicolai},
      title        = {{A}myloid‐induced neuronal hyperactivity and
                      ‐metabolism are associated with faster tau accumulation in
                      {A}lzheimer's {D}isease},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {Suppl 2},
      issn         = {1552-5260},
      reportid     = {DZNE-2025-01470},
      pages        = {e099685},
      year         = {2025},
      abstract     = {The link between amyloid (Aβ) and tau accumulation in
                      Alzheimer's disease (AD) is still unknown, hindering
                      therapeutic efforts to attenuate the Aβ-tau axis.
                      Preclinical studies demonstrated that Aβ promotes
                      hyperexcitatory neuronal activity and that tau spreads
                      trans-synaptically in an activity-dependent manner. We
                      recently showed that tau spreads across connected brain
                      regions, and that Aβ-related connectivity increases promote
                      tau spreading (Roemer-Cassiano et al., 2024). Yet, it is
                      unclear whether Aβ-related hyperconnectivity indeed
                      represents hyperexcitatory neuronal activity. To test this,
                      we combined resting-state fMRI, FDG-PET and post-mortem
                      data, to determine whether Aβ promotes neuronal
                      hyperactivity, thereby driving tau spread in AD.We first
                      assessed the effect Aβ on neuronal hyperactivity with a
                      novel algorithm to estimate the excitatory to inhibitory
                      (E/I) ratio applied to resting-state fMRI in 145
                      amyloid-negative controls and 441 amyloid-positive subjects
                      across the AD spectrum, who also underwent amyloid-PET.
                      Second, we used glucose metabolism (FDG-PET) as a marker of
                      neuronal activity in 638 amyloid-positive AD spectrum
                      patients, with a subset (n = 215) of them having tau-PET at
                      a later timepoint. Lastly, we analysed post-mortem data of 5
                      AD patients and 4 controls stained for c-Fos as a marker of
                      ante-mortem neuronal activity.Resting-state fMRI-based
                      E/I-ratio assessment in Aβ- controls showed biologically
                      plausible stronger inhibition in association cortices
                      (Figure 1A). In AD, we found an association between higher
                      amyloid-PET SUVRs and a higher E/I ratio, consistent across
                      diagnostic groups (Figure 1B-D), indicative of
                      Aβ-associated hyperexcitatory neuronal activity. Second, we
                      found within individuals, that higher regional amyloid-PET
                      was linked to higher FDG-PET (correlationamyloid-PET vs.
                      FDG-PET: $95\%$ CI [0.37,0.40] p-value <0.001), suggesting
                      higher neuronal activity in Aβ-harbouring regions (Figure
                      2A). Similarly, we found post-mortem elevated neuronal c-Fos
                      expression in AD brain tissue vs. controls, indicating
                      higher ante-mortem neuronal activity (Figure 3G). Finally,
                      we found that amyloid-PET-based prediction of subject-level
                      future tau accumulation is improved when including regional
                      FDG-PET (Figure 2B) and that FDG-PET-assessed
                      hypermetabolism mediates subject-level effects of Aβ on
                      subsequent tau accumulation (Figure 2C).Aβ promotes an
                      hyper-excitatory shift in neuronal activity that manifests
                      in glucose hypermetabolism which promotes Aβ-related tau
                      accumulation. Thus, Aβ-associated neuronal
                      hyper-excitability is a potential target for attenuating the
                      Ab-tau axis in AD.},
      month         = {Jul},
      date          = {2025-07-27},
      organization  = {Alzheimer’s Association
                       International Conference, Toronto
                       (Canada), 27 Jul 2025 - 31 Jul 2025},
      keywords     = {Humans / Alzheimer Disease: metabolism / Alzheimer Disease:
                      diagnostic imaging / Alzheimer Disease: pathology /
                      Positron-Emission Tomography / Female / Male / Biomarkers:
                      metabolism / Magnetic Resonance Imaging / Aged / tau
                      Proteins: metabolism / Amyloid beta-Peptides: metabolism /
                      Brain: metabolism / Brain: diagnostic imaging / Brain:
                      pathology / Fluorodeoxyglucose F18 / Neurons: metabolism /
                      Aged, 80 and over / Biomarkers (NLM Chemicals) / tau
                      Proteins (NLM Chemicals) / Amyloid beta-Peptides (NLM
                      Chemicals) / Fluorodeoxyglucose F18 (NLM Chemicals)},
      cin          = {AG Simons / AG Dichgans / Clinical Research (Munich) / AG
                      Haass},
      ddc          = {610},
      cid          = {I:(DE-2719)1110008 / I:(DE-2719)5000022 /
                      I:(DE-2719)1111015 / I:(DE-2719)1110007},
      pnm          = {351 - Brain Function (POF4-351) / 353 - Clinical and Health
                      Care Research (POF4-353) / 352 - Disease Mechanisms
                      (POF4-352)},
      pid          = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-353 /
                      G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      pubmed       = {pmid:41445344},
      pmc          = {pmc:PMC12739343},
      doi          = {10.1002/alz70856_099685},
      url          = {https://pub.dzne.de/record/283063},
}