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@ARTICLE{Dzel:164071,
      author       = {Düzel, Emrah and Ziegler, Gabriel and Berron, David and
                      Maaß, Anne and Schütze, Hartmut and Cardenas-Blanco,
                      Arturo and Glanz, Wenzel and Metzger, Coraline and Dobisch,
                      Laura and Reuter, Martin and Spottke, Annika and Brosseron,
                      Frederic and Fliessbach, Klaus and Heneka, Michael T and
                      Laske, Christoph and Peters, Oliver and Priller, Josef and
                      Spruth, Eike Jakob and Ramirez, Alfredo and Speck, Oliver
                      and Schneider, Anja and Teipel, Stefan and Kilimann, Ingo
                      and Wiltfang, Jens and Schott, Björn and Preis, Lukas and
                      Gref, Daria and Maier, Franziska and Munk, Matthias H and
                      Roy, Nina and Ballarini, Tomasso and Yakupov, Renat and
                      Haynes, John Dylan and Dechent, Peter and Scheffler, Klaus
                      and Wagner, Michael and Jessen, Frank},
      title        = {{A}myloid pathology but not {APOE} ε4 status is permissive
                      for tau-related hippocampal dysfunction.},
      journal      = {Brain},
      volume       = {145},
      number       = {4},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2022-00734},
      pages        = {1473-1485},
      year         = {2022},
      note         = {(CC BY-NC)},
      abstract     = {We investigated whether the impact of tau-pathology on
                      memory performance and on hippocampal/medial temporal memory
                      function in non-demented individuals depends on the presence
                      of amyloid pathology, irrespective of diagnostic clinical
                      stage. We conducted a cross-sectional analysis of the
                      observational, multicentric DZNE-Longitudinal Cognitive
                      Impairment and Dementia Study (DELCODE). Two hundred and
                      thirty-five participants completed task functional MRI and
                      provided CSF (92 cognitively unimpaired, 100 experiencing
                      subjective cognitive decline and 43 with mild cognitive
                      impairment). Presence (A+) and absence (A-) of amyloid
                      pathology was defined by CSF amyloid-β42 (Aβ42) levels.
                      Free recall performance in the Free and Cued Selective
                      Reminding Test, scene recognition memory accuracy and
                      hippocampal/medial temporal functional MRI novelty responses
                      to scene images were related to CSF total-tau and
                      phospho-tau levels separately for A+ and A- individuals. We
                      found that total-tau and phospho-tau levels were negatively
                      associated with memory performance in both tasks and with
                      novelty responses in the hippocampus and amygdala, in
                      interaction with Aβ42 levels. Subgroup analyses showed that
                      these relationships were only present in A+ and remained
                      stable when very high levels of tau (>700 pg/ml) and
                      phospho-tau (>100 pg/ml) were excluded. These relationships
                      were significant with diagnosis, age, education, sex,
                      assessment site and Aβ42 levels as covariates. They also
                      remained significant after propensity score based matching
                      of phospho-tau levels across A+ and A- groups. After
                      classifying this matched sample for phospho-tau pathology
                      (T-/T+), individuals with A+/T+ were significantly more
                      memory-impaired than A-/T+ despite the fact that both groups
                      had the same amount of phospho-tau pathology. ApoE status
                      (presence of the E4 allele), a known genetic risk factor for
                      Alzheimer's disease, did not mediate the relationship
                      between tau pathology and hippocampal function and memory
                      performance. Thus, our data show that the presence of
                      amyloid pathology is associated with a linear relationship
                      between tau pathology, hippocampal dysfunction and memory
                      impairment, although the actual severity of amyloid
                      pathology is uncorrelated. Our data therefore indicate that
                      the presence of amyloid pathology provides a permissive
                      state for tau-related hippocampal dysfunction and
                      hippocampus-dependent recognition and recall impairment.
                      This raises the possibility that in the predementia stage of
                      Alzheimer's disease, removing the negative impact of amyloid
                      pathology could improve memory and hippocampal function even
                      if the amount of tau-pathology in CSF is not changed,
                      whereas reducing increased CSF tau-pathology in
                      amyloid-negative individuals may not proportionally improve
                      memory function.},
      keywords     = {Alzheimer Disease: pathology / Amyloid beta-Peptides:
                      metabolism / Amyloidogenic Proteins / Amyloidosis /
                      Apolipoproteins E: genetics / Biomarkers / Cognitive
                      Dysfunction: diagnosis / Cognitive Dysfunction: genetics /
                      Cross-Sectional Studies / Hippocampus: metabolism / Humans /
                      tau Proteins: metabolism / Alzheimer’s disease biomarker
                      (Other) / hippocampus (Other) / memory (Other) / mild
                      cognitive impairment (Other) / subjective cognitive decline
                      (Other)},
      cin          = {AG Düzel / AG Jessen / AG Berron / AG Speck / KAP /
                      Magdeburg common / AG Reuter / AG Klockgether / Biomarker /
                      Patient Studies Bonn / Core ICRU / AG Endres / AG Schneider
                      / AG Teipel / AG Wiltfang / AG Fischer / AG Gasser /
                      Clinical Research Platform (CRP) / AG Wagner / Delcode},
      ddc          = {610},
      cid          = {I:(DE-2719)5000006 / I:(DE-2719)1011102 /
                      I:(DE-2719)5000070 / I:(DE-2719)1340009 / I:(DE-2719)1340013
                      / I:(DE-2719)6000015 / I:(DE-2719)1040310 /
                      I:(DE-2719)1011001 / I:(DE-2719)1011301 / I:(DE-2719)1011101
                      / I:(DE-2719)1240005 / I:(DE-2719)1811005 /
                      I:(DE-2719)1011305 / I:(DE-2719)1510100 / I:(DE-2719)1410006
                      / I:(DE-2719)1410002 / I:(DE-2719)1210000 /
                      I:(DE-2719)1011401 / I:(DE-2719)1011201 /
                      I:(DE-2719)5000034},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 354 -
                      Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-354},
      experiment   = {EXP:(DE-2719)DELCODE-20140101},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9128811},
      pubmed       = {pmid:35352105},
      doi          = {10.1093/brain/awab405},
      url          = {https://pub.dzne.de/record/164071},
}