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@INPROCEEDINGS{Hirsch:283109,
      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       = {S2},
      issn         = {1552-5260},
      reportid     = {DZNE-2026-00005},
      pages        = {e098847},
      year         = {2025},
      abstract     = {Background: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).Method: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.Result: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.Conclusion: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},
      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},
      doi          = {10.1002/alz70856_098847},
      url          = {https://pub.dzne.de/record/283109},
}