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@INPROCEEDINGS{Steward:283154,
      author       = {Steward, Anna and Dewenter, Anna and Roemer-Cassiano,
                      Sebastian and Biel, Davina and Zhu, Zeyu and Frontzkowski,
                      Lukas and Hirsch, Fabian and Klonowksi, Madleen and
                      Gnoerich, Johannes and Dehsarvi, Amir and Brendel, Matthias
                      and Franzmeier, Nicolai},
      title        = {{A}po{E}4 accelerates p ‐tau driven tau aggregation and
                      spread in {A}lzheimer's {D}isease in a allele‐dose
                      dependent manner},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {S2},
      issn         = {1552-5260},
      reportid     = {DZNE-2026-00050},
      pages        = {e105476},
      year         = {2025},
      abstract     = {Background: Understanding factors influencing Alzheimer's
                      disease (AD) progression is crucial for optimising treatment
                      timing and targets. A major genetic risk factor, the
                      Apolipoprotein E ε4 allele (ApoE4), is associated with
                      earlier tau pathology accumulation and spread at lower
                      amyloid-beta (Aβ) levels (Steward, JAMA Neurol, 2023).
                      However, the mechanisms underlying this association remain
                      unclear (Figure 1A). Therefore, we assessed how ApoE4
                      accelerates Aβ-related tau aggregation. Specifically, we
                      investigated whether ApoE4 promotes Aβ-driven secretion of
                      phospho tau (p-tau) or ptau dependent tau aggregation, and
                      determined whether ApoE4 promotes tau pathology in an allele
                      dose-dependent manner. Method: We analysed data from
                      APOE-genotyped AD-spectrum participants in the ADNI (n =
                      201) and A4 cohorts (n = 200), integrating cross-sectional
                      fluid biomarker measures (plasma ptau217, CSF ptau181) and
                      longitudinal Flortaucipir tau-PET and
                      Florbetaben/Florbetapir amyloid-PET. Using linear
                      regression, we assessed whether the interaction between
                      amyloid-PET and ApoE4 allele dosage influences plasma
                      ptau217, and replicated this analysis with CSF ptau181 in an
                      ADNI subset (n = 115). Secondly, to investigate whether
                      ApoE4 enhances tau fibrilisation and spread, we calculated
                      annual tau-PET SUVR accumulation rates across a
                      connectivity-based tau spreading stages, using our prior
                      methodology (e.g. Franzmeier, Sci Adv, 2020). Linear
                      regressions tested the interaction between ptau217 (or CSF
                      ptau181) and ApoE4 allele count on connectivity-mediated
                      tau-PET accumulation in four connectivity stages that
                      capture progressive tau spread. Result: ApoE4 allele dosage
                      did not moderate the relationship between amyloid-PET and
                      plasma ptau217 in either sample (Figure 1B, ADNI: β=0.13, p
                      = 0.32; A4: β=-0.20, p = 0.17) nor between amyloid-PET and
                      CSF ptau181 in ADNI subsample (Figure 1B, b=-.16, p = 0.42).
                      However, a significant ApoE4 allele dose effect was observed
                      in moderating the relationship between plasma ptau217 and
                      tau-PET accumulation across connectivity stages independent
                      of amyloid burden (Figure 1C, ADNI: Q1–4 mean β=0.44,
                      Q1-4 p <0.001; A4: Q1-4 mean β = 0.56, Q1,2,4 p <0.001, Q3
                      p <0.05), with the strongest effect in individuals carrying
                      two ApoE4 alleles. Conclusion: ApoE4 exerts an allele
                      dose-dependent effect on ptau induced tau aggregation,
                      driving accelerated tau spreading at lower Aβ levels. This
                      suggests that attenuating soluble ptau increases in ApoE4
                      carriers may mitigate downstream tau fibrilisation and delay
                      dementia onset, highlighting the potential of personalised
                      therapeutic approaches.},
      month         = {Jul},
      date          = {2025-07-27},
      organization  = {Alzheimer’s Association
                       International Conference, Toronto
                       (Canada), 27 Jul 2025 - 31 Jul 2025},
      keywords     = {Humans / tau Proteins: cerebrospinal fluid / tau Proteins:
                      metabolism / tau Proteins: blood / Alzheimer Disease:
                      genetics / Alzheimer Disease: diagnostic imaging / Alzheimer
                      Disease: cerebrospinal fluid / Alzheimer Disease: metabolism
                      / Biomarkers: cerebrospinal fluid / Biomarkers: blood /
                      Female / Male / Apolipoprotein E4: genetics / Amyloid
                      beta-Peptides: metabolism / Amyloid beta-Peptides:
                      cerebrospinal fluid / Aged / Positron-Emission Tomography /
                      Aged, 80 and over / Cross-Sectional Studies / Alleles /
                      Brain: diagnostic imaging / Brain: metabolism / tau Proteins
                      (NLM Chemicals) / Biomarkers (NLM Chemicals) /
                      Apolipoprotein E4 (NLM Chemicals) / Amyloid beta-Peptides
                      (NLM Chemicals) / MAPT protein, human (NLM Chemicals)},
      cin          = {AG Haass},
      ddc          = {610},
      cid          = {I:(DE-2719)1110007},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      doi          = {10.1002/alz70856_105476},
      url          = {https://pub.dzne.de/record/283154},
}