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@ARTICLE{Schultz:259715,
      author       = {Schultz, Stephanie A and Shirzadi, Zahra and Schultz, Aaron
                      P and Liu, Lei and Fitzpatrick, Colleen D and McDade, Eric
                      and Barthelemy, Nicolas R and Renton, Alan and Esposito,
                      Bianca and Joseph-Mathurin, Nelly and Cruchaga, Carlos and
                      Chen, Charles D and Goate, Alison and Allegri, Ricardo
                      Francisco and Benzinger, Tammie L S and Berman, Sarah and
                      Chui, Helena C and Fagan, Anne M and Farlow, Martin R and
                      Fox, Nick C and Gordon, Brian A and Day, Gregory S and
                      Graff-Radford, Neill R and Hassenstab, Jason J and Hanseeuw,
                      Bernard J and Hofmann, Anna and Jack, Clifford R and Jucker,
                      Mathias and Karch, Celeste M and Koeppe, Robert A and Lee,
                      Jae-Hong and Levey, Allan I and Levin, Johannes and Martins,
                      Ralph N and Mori, Hiroshi and Morris, John C and Noble,
                      James and Perrin, Richard J and Rosa-Neto, Pedro and
                      Salloway, Stephen P and Sanchez-Valle, Raquel and Schofield,
                      Peter R and Xiong, Chengjie and Johnson, Keith A and
                      Bateman, Randall J and Sperling, Reisa A and Chhatwal,
                      Jasmeer P},
      collaboration = {Investigators, Dominantly Inherited Alzheimer Network},
      title        = {{L}ocation of pathogenic variants in {PSEN}1 impacts
                      progression of cognitive, clinical, and neurodegenerative
                      measures in autosomal-dominant {A}lzheimer's disease.},
      journal      = {Aging cell},
      volume       = {22},
      number       = {8},
      issn         = {1474-9718},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2023-00787},
      pages        = {e13871},
      year         = {2023},
      abstract     = {Although pathogenic variants in PSEN1 leading to
                      autosomal-dominant Alzheimer disease (ADAD) are highly
                      penetrant, substantial interindividual variability in the
                      rates of cognitive decline and biomarker change are observed
                      in ADAD. We hypothesized that this interindividual
                      variability may be associated with the location of the
                      pathogenic variant within PSEN1. PSEN1 pathogenic variant
                      carriers participating in the Dominantly Inherited Alzheimer
                      Network (DIAN) observational study were grouped based on
                      whether the underlying variant affects a transmembrane (TM)
                      or cytoplasmic (CY) protein domain within PSEN1. CY and TM
                      carriers and variant non-carriers (NC) who completed
                      clinical evaluation, multimodal neuroimaging, and lumbar
                      puncture for collection of cerebrospinal fluid (CSF) as part
                      of their participation in DIAN were included in this study.
                      Linear mixed effects models were used to determine
                      differences in clinical, cognitive, and biomarker measures
                      between the NC, TM, and CY groups. While both the CY and TM
                      groups were found to have similarly elevated Aβ compared to
                      NC, TM carriers had greater cognitive impairment, smaller
                      hippocampal volume, and elevated phosphorylated tau levels
                      across the spectrum of pre-symptomatic and symptomatic
                      phases of disease as compared to CY, using both
                      cross-sectional and longitudinal data. As distinct portions
                      of PSEN1 are differentially involved in APP processing by
                      γ-secretase and the generation of toxic β-amyloid species,
                      these results have important implications for understanding
                      the pathobiology of ADAD and accounting for a substantial
                      portion of the interindividual heterogeneity in ongoing ADAD
                      clinical trials.},
      keywords     = {Male / Humans / Alzheimer Disease: genetics / Alzheimer
                      Disease: metabolism / Cross-Sectional Studies / Amyloid
                      beta-Peptides: genetics / Amyloid beta-Peptides: metabolism
                      / Biomarkers / Presenilin-1: genetics / Cognition / Mutation
                      / Female / Adult / Brain: metabolism / Brain: pathology /
                      Positron-Emission Tomography / Magnetic Resonance Imaging /
                      Presenilin-1: chemistry / Presenilin-1: metabolism /
                      Alzheimer Disease: pathology / tau Proteins: metabolism /
                      Longitudinal Studies / PSEN1 (Other) / tau Proteins (NLM
                      Chemicals) / PSEN1 (Other) / Presenilin-1 (Other) /
                      Autosomal dominant Alzheimer disease (ADAD) (Other) /
                      heterogeneity (Other) / neurodegeneration (Other) / Amyloid
                      beta-Peptides (NLM Chemicals) / Biomarkers (NLM Chemicals) /
                      Presenilin-1 (NLM Chemicals) / PSEN1 protein, human (NLM
                      Chemicals) / Presenilin-1 (Other)},
      cin          = {AG Gasser / AG Jucker / AG Levin / Clinical Research
                      (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)1210001 /
                      I:(DE-2719)1111016 / I:(DE-2719)1111015},
      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},
      experiment   = {EXP:(DE-2719)DIAN-20090101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37291760},
      pmc          = {pmc:PMC10410059},
      doi          = {10.1111/acel.13871},
      url          = {https://pub.dzne.de/record/259715},
}