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@INPROCEEDINGS{Valentim:283094,
      author       = {Valentim, Carolina and Denecke, Jannis and Frerich, Simon
                      and Malik, Rainer and Franzmeier, Nicolai and Ewers,
                      Michael},
      title        = {{P}olygenic risk scores modify the association between
                      amyloid and tau {PET} accumulation in patients with
                      {A}lzheimer’s disease},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {Suppl 8},
      issn         = {1552-5260},
      reportid     = {DZNE-2025-01501},
      pages        = {e110860},
      year         = {2025},
      abstract     = {Genome-wide association studies (GWAS) have identified a
                      larger number of genetic variants that are associated with
                      increased risk of AD dementia. The biological pathways that
                      underlie the link between SNPs and the development of core
                      AD pathologies remain however unclear. Here, we generated
                      pathway-specific polygenic risk scores to test their
                      modulating effect on the association between amyloid-beta
                      (Aβ) chronicity and tau deposition in patients with AD.We
                      analysed 295 amyloid-PET-positive participants from ADNI
                      (mean age 76.5 ± 7.6; 165 CU, 85 MCI, 45 Dementia) with
                      cross-sectional genetic, cognitive, and tau-PET (AV1451) and
                      Aβ-PET (Florbetapir and Florbetaben) data. We identified in
                      a meta-analysis of recent genome-wide association studies
                      (GWAS) 388 independent SNPs associated with AD. We computed
                      six pathway-specific PRS based on gene set enrichment
                      analysis identifying the pathways implicating amyloid beta,
                      immune activation, endocytosis/transport, clearance and
                      signal transduction (Figure 1). Aβ-chronicity was estimated
                      using the Sampled Iterative Local Approximation (SILA)
                      technique (Betthauser et al., 2022), which infers the
                      temporal trajectory and extent of amyloid accumulation by
                      aligning PET-derived amyloid burden across longitudinal data
                      points. Robust linear regression (Huber method) models
                      assessed interactions between SILA-derived Aβ-chronicity
                      and tau-PET uptake in Braak-stage ROIs (I, III-IV, and
                      V-VI), controlling APOE-ε4 status, age, sex and education.
                      Outliers were defined as three standard deviations from the
                      mean.Significant interactions between Aβ-chronicity and
                      pathway-PRS for amyloid beta and endocytosis/transport were
                      observed, with higher genetic risk amplifying the
                      association between longer amyloid exposure and tau
                      accumulation in Braak-stage ROIs III-IV $\&$ V-VI (p <
                      0.03). Effects remained significant after the removal of
                      predefined outliers (p < 0.02).Our findings indicate that
                      genetic variations, particularly within the amyloid-beta and
                      endocytosis/transport pathways, strengthen the association
                      between longer amyloid exposure and increased tau pathology.
                      The significance of the amyloid-beta pathway suggests a
                      direct genetic contribution to amyloid-driven tau
                      accumulation, whereas the endocytosis/transport pathway
                      findings support the hypothesis that amyloid-tau
                      interactions at the synaptic level drive AD progression.
                      These results align with prior evidence on mechanistic links
                      between amyloid and tau pathology 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: genetics / Alzheimer Disease:
                      diagnostic imaging / Alzheimer Disease: metabolism / Male /
                      Aged / Female / Genome-Wide Association Study /
                      Positron-Emission Tomography / Amyloid beta-Peptides:
                      metabolism / tau Proteins: metabolism / Aged, 80 and over /
                      Cross-Sectional Studies / Polymorphism, Single Nucleotide /
                      Brain: diagnostic imaging / Brain: metabolism / Aniline
                      Compounds / Ethylene Glycols / Amyloid beta-Peptides (NLM
                      Chemicals) / tau Proteins (NLM Chemicals) / Aniline
                      Compounds (NLM Chemicals) / florbetapir (NLM Chemicals) /
                      Ethylene Glycols (NLM Chemicals)},
      cin          = {Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      pubmed       = {pmid:41433394},
      pmc          = {pmc:PMC12725496},
      doi          = {10.1002/alz70862_110860},
      url          = {https://pub.dzne.de/record/283094},
}