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@INPROCEEDINGS{Hirsch:283098,
      author       = {Hirsch, Fabian and Frontzkowski, Lukas and Roemer-Cassiano,
                      Sebastian and Dehsarvi, Amir and Steward, Anna and Dewenter,
                      Anna and Biel, Davina and Klonowksi, Madleen and Zhu, Zeyu
                      and Gnoerich, Johannes and Schöll, Michael and Höglinger,
                      Günter U and Brendel, Matthias and Franzmeier, Nicolai},
      title        = {{C}onnector {H}ubs {A}ccelerate the {S}pread of {T}au
                      {P}athology in {A}lzheimer's {D}isease},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {Suppl 8},
      issn         = {1552-5260},
      reportid     = {DZNE-2025-01505},
      pages        = {e109933},
      year         = {2025},
      abstract     = {Tau accumulation drives neurodegeneration and cognitive
                      decline in Alzheimer's Disease (AD) and preclinical research
                      suggests that tau spreads transsynaptically across connected
                      neurons. We translated tau spreading models to human
                      neuroimaging data, showing that tau pathology spreads from
                      circumscribed epicenters to connected regions in AD,
                      following the architecture of functional brain networks. To
                      further determine whether the topology of brain networks
                      influences tau spreading dynamics, we investigated whether
                      functional hubs (i.e. regions with strong inter-regional
                      connections) accelerate tau spread in AD. Specifically, we
                      hypothesized that more efficient communication from tau
                      epicenters towards hubs that cross-link large-scale brain
                      networks (connector hubs) rather than hubs that interconnect
                      neighboring regions (local hubs) accelerates amyloid-related
                      tau accumulation and cognitive decline (Figure
                      1).Longitudinal tau/amyloid-PET and cognitive data from two
                      independent cohorts covering the AD spectrum (ADNI/A4 n =
                      325/220) were analyzed to examine amyloid-driven
                      spatiotemporal tau accumulation patterns and cognitive
                      decline. Structural- and functional-connectivity templates
                      from healthy controls were used to model the connectional
                      efficiency of subject-level tau epicenters (i.e. $10\%$ of
                      brain regions with highest baseline tau-PET) towards
                      connector/local hubs (Figure 2). Using robust regression, we
                      then tested whether more efficient communication of
                      subject-level tau epicenters to connector vs. local hubs
                      accelerated global tau accumulation, cognitive decline, and
                      tau dissemination across networks.Supporting our hypotheses,
                      we found that the effect of higher baseline amyloid-PET on
                      faster global tau-PET increases was moderated by more
                      efficient communication of tau epicenters towards connector
                      relative to local hubs (ADNI/A4: β = 0.31/0.40,
                      p<0.001/0.03), such that subjects with stronger epicenter
                      communication to connector hubs showed an amplified effect
                      of amyloid on global tau accumulation rates (Figure 3A). The
                      same interaction models also predicted faster cognitive
                      decline (ADNI/A4: β = -0.49/-0.34, p<0.001/0.04, Figure
                      3B), and larger extents of tau dissemination across
                      functional networks (ADNI/A4: β = 0.6/0.36, p<0.001/0.04).
                      All p-values were FDR-corrected.Brain network topology
                      shapes spatiotemporal tau accumulation rates and cognitive
                      trajectories in AD. Specifically, stronger communication of
                      tau epicenters with connector hubs that are characterized by
                      widespread cross-network connections amplifies
                      amyloid-related tau accumulation. This suggests that brain
                      network architecture has a profound modulating impact on tau
                      aggregation and disease progression 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: diagnostic imaging / Alzheimer
                      Disease: metabolism / Alzheimer Disease: pathology / tau
                      Proteins: metabolism / Positron-Emission Tomography / Brain:
                      diagnostic imaging / Brain: metabolism / Brain: pathology /
                      Male / Female / Aged / Cognitive Dysfunction: diagnostic
                      imaging / Cognitive Dysfunction: metabolism / Neuroimaging /
                      Longitudinal Studies / Aged, 80 and over / tau Proteins (NLM
                      Chemicals)},
      cin          = {Clinical Research (Munich) / AG Haass},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015 / I:(DE-2719)1110007},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      pubmed       = {pmid:41433910},
      pmc          = {pmc:PMC12724848},
      doi          = {10.1002/alz70862_109933},
      url          = {https://pub.dzne.de/record/283098},
}