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@ARTICLE{deBruin:281875,
      author       = {de Bruin, Hannah and Groot, Colin and Barthel, Henryk and
                      Bischof, Gérard N and Blazhenets, Ganna and Boellaard,
                      Ronald and Boon, Baayla D C and Brendel, Matthias and Cash,
                      David M and Coath, William and Day, Gregory S and Dickerson,
                      Bradford C and Doering, Elena and Drzezga, Alexander and van
                      Dyck, Christopher H and Eimeren, Thilo and van der Flier,
                      Wiesje M and Fredericks, Carolyn A and Fryer, Tim D and van
                      de Giessen, Elsmarieke and Gordon, Brian A and
                      Graff-Radford, Jonathan and Grinberg, Lea T and Hansson,
                      Oskar and Hobbs, Diana A and Hoenig, Merle C and Höglinger,
                      Günter and Irwin, David J and Jones, P Simon and Josephs,
                      Keith A and Katsumi, Yuta and La Joie, Renaud and Lee,
                      Edward B and Levin, Johannes and Malpetti, Maura and
                      McGinnis, Scott M and Mecca, Adam P and Mohanty, Rosaleena
                      and Nasrallah, Ilya M and O'Brien, John T and O'Dell, Ryan S
                      and Palleis, Carla and Perneczky, Robert and Phillips,
                      Jeffrey S and Putcha, Deepti and Rabinovici, Gil D and
                      Rahmouni, Nesrine and Rosa-Neto, Pedro and Rowe, James B and
                      Rullmann, Michael and Sabri, Osama and Saur, Dorothee and
                      Schildan, Andreas and Schott, Jonathan M and Schroeter,
                      Matthias L and Seeley, William W and Servaes, Stijn and
                      Sintini, Irene and Smith, Ruben and Spina, Salvatore and
                      Stevenson, Jenna and Stomrud, Erik and Strandberg, Olof and
                      Therriault, Joseph and Tideman, Pontus and Touroutoglou,
                      Alexandra and Trainer, Anne E and Visser, Denise and
                      Wekselman, Fattin and Weston, Philip S J and Whitwell,
                      Jennifer L and Wolk, David A and Yong, Keir and Pijnenburg,
                      Yolande A L and Franzmeier, Nicolai and Ossenkoppele, Rik},
      title        = {{C}onnectivity as a universal predictor of tau progression
                      in atypical {A}lzheimer's disease.},
      journal      = {Brain},
      volume       = {148},
      number       = {11},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2025-01246},
      pages        = {3893 - 3912},
      year         = {2025},
      abstract     = {The link between regional tau load and clinical
                      manifestation of Alzheimer's disease (AD) highlights the
                      importance of characterizing spatial tau distribution across
                      disease variants. In typical (memory-predominant) AD, the
                      spatial progression of tau pathology mirrors the functional
                      connections from temporal lobe epicentres. However, given
                      the limited spatial heterogeneity of tau in typical AD,
                      atypical (non-amnestic-predominant) AD variants with
                      distinct tau patterns provide a key opportunity to
                      investigate the universality of connectivity as a scaffold
                      for tau progression. In this large-scale, multicentre study
                      across 14 international sites, we included cross-sectional
                      tau-PET data from 320 individuals with atypical AD (n = 139
                      posterior cortical atrophy/PCA-AD; n = 103 logopenic variant
                      primary progressive aphasia/lvPPA-AD; n = 35 behavioural
                      variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with
                      a subset of individuals (n = 78) having longitudinal tau-PET
                      data. Additionally, as an independent sample, we included
                      regional post-mortem tau stainings from 93 atypical AD
                      patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n =
                      23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used
                      to harmonize different tau-PET tracers by transforming
                      tau-PET standardized uptake value ratios to tau positivity
                      probabilities (a uniform scale ranging from $0\%$ to
                      $100\%).$ Using linear regression, we assessed whether brain
                      regions with stronger resting-state functional MRI-based
                      functional connectivity, derived from healthy elderly
                      controls in the Alzheimer's Disease Neuroimaging Initiative
                      (ADNI), showed greater covariance in cross-sectional and
                      longitudinal tau-PET and post-mortem tau pathology.
                      Furthermore, we examined whether functional connectivity of
                      tau-PET epicentres (i.e. the top $5\%$ of regions with the
                      highest baseline tau load) and tau-PET accumulation
                      epicentres (i.e. the top $5\%$ of regions with the highest
                      tau accumulation rates) was associated with cross-sectional
                      and longitudinal tau patterns. Our findings show that
                      tau-PET epicentres aligned with clinical variants, e.g. a
                      visual network predominant pattern in PCA-AD ('visual AD')
                      and left-hemispheric temporal predominance, particularly
                      within the language network, in lvPPA-AD ('language AD').
                      Moreover, more strongly functionally connected regions
                      showed correlated concurrent tau-PET levels (confirmed with
                      post-mortem data) and tau-PET accumulation rates. The
                      functional connectivity profile of tau-PET epicentres and
                      accumulation epicentres corresponded to tau-PET progression
                      patterns, with higher tau-PET levels and accumulation rates
                      in functionally close regions, and lower tau-PET levels and
                      accumulation rates in functionally distant regions. Our data
                      are consistent with the hypothesis that tau propagation
                      occurs along functional connections originating from local
                      epicentres, across all AD clinical variants. Since tau
                      proteinopathy is a major driver of neurodegeneration and
                      cognitive decline, this finding may advance personalized
                      medicine and participant-specific end points in clinical
                      trials.},
      keywords     = {Humans / Alzheimer Disease: diagnostic imaging / Alzheimer
                      Disease: metabolism / Alzheimer Disease: pathology / Female
                      / Male / Disease Progression / Aged / tau Proteins:
                      metabolism / Positron-Emission Tomography / Cross-Sectional
                      Studies / Middle Aged / Aged, 80 and over / Brain:
                      diagnostic imaging / Brain: metabolism / Brain: pathology /
                      Magnetic Resonance Imaging / Longitudinal Studies / PET
                      (Other) / atypical Alzheimer's disease (Other) /
                      connectivity (Other) / fMRI (Other) / heterogeneity (Other)
                      / tau (Other) / tau Proteins (NLM Chemicals)},
      cin          = {AG Haass / AG Boecker / Clinical Research (Munich) / AG
                      Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1011202 /
                      I:(DE-2719)1111015 / I:(DE-2719)1111016},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40810361},
      pmc          = {pmc:PMC12588720},
      doi          = {10.1093/brain/awaf279},
      url          = {https://pub.dzne.de/record/281875},
}