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@ARTICLE{Wagemann:269526,
      author       = {Wagemann, Olivia and Liu, Haiyan and Wang, Guoqiao and Shi,
                      Xinyu and Bittner, Tobias and Scelsi, Marzia A. and Farlow,
                      Martin R. and Clifford, David B. and Supnet-Bell, Charlene
                      and Santacruz, Anna M. and Aschenbrenner, Andrew J. and
                      Hassenstab, Jason J. and Benzinger, Tammie L. S. and Gordon,
                      Brian A. and Coalier, Kelley A. and Cruchaga, Carlos and
                      Ibanez, Laura and Perrin, Richard J. and Xiong, Chengjie and
                      Li, Yan and Morris, John C. and Lah, James J. and Berman,
                      Sarah B. and Roberson, Erik D. and van Dyck, Christopher H.
                      and Galasko, Douglas and Gauthier, Serge and Hsiung,
                      Ging-Yuek R. and Brooks, William S. and Pariente, Jérémie
                      and Mummery, Catherine J. and Day, Gregory S. and Ringman,
                      John M. and Mendez, Patricio Chrem and St. George-Hyslop,
                      Peter and Fox, Nick C. and Suzuki, Kazushi and Okhravi,
                      Hamid R. and Chhatwal, Jasmeer and Levin, Johannes and
                      Jucker, Mathias and Sims, John R. and Holdridge, Karen C.
                      and Proctor, Nicholas K. and Yaari, Roy and Andersen, Scott
                      W. and Mancini, Michele and Llibre-Guerra, Jorge and
                      Bateman, Randall J. and McDade, Eric and Daniels, Alisha J.
                      and Courtney, Laura and Xu, Xiong and Lu, Ruijin and
                      Gremminger, Emily and Franklin, Erin and Ibanez, Laura and
                      Jerome, Gina and Herries, Elizabeth and Stauber, Jennifer
                      and Baker, Bryce and Minton, Matthew and Goate, Alison M.
                      and Renton, Alan E. and Picarello, Danielle M. and Hornbeck,
                      Russ and Chen, Allison and Chen, Charles and Flores, Shaney
                      and Joseph-Mathurin, Nelly and Jarman, Steve and Jackson,
                      Kelley and Keefe, Sarah and Koudelis, Deborah and
                      Massoumzadeh, Parinaz and McCullough, Austin and McKay,
                      Nicole and Nicklaus, Joyce and Pulizos, Christine and Wang,
                      Qing and Sabaredzovic, Edita and Smith, Hunter and Scott,
                      Jalen and Simmons, Ashlee and Rizzo, Jacqueline and Smith,
                      Jennifer and Stout, Sarah and Karch, Celeste M. and Marsh,
                      Jacob and Holtzman, David M. and Barthelemy, Nicolas and Xu,
                      Jinbin and Noble, James M. and Ikonomovic, Snezana and
                      Nadkarni, Neelesh K. and Graff-Radford, Neill R. and
                      Ikeuchi, Takeshi and Kasuga, Kensaku and Niimi, Yoshiki and
                      Huey, Edward D. and Salloway, Stephen and Schofield, Peter
                      R. and Bechara, Jacob A. and Martins, Ralph and Cash, David
                      M. and Ryan, Natalie S. and Laske, Christoph and Hofmann,
                      Anna and Kuder-Buletta, Elke and Gräber-Sultan, Susanne and
                      Obermueller, Ulrike and Rödenbeck, Yvonne Esther and
                      Vӧglein, Jonathan and Lee, Jae-Hong and Roh, Jee Hoon and
                      Sanchez-Valle, Raquel and Rosa-Neto, Pedro and Allegri,
                      Ricardo F. and Surace, Ezequiel and Vazquez, Silvia and
                      Lopera, Francisco and Leon, Yudy Milena and Ramirez, Laura
                      and Aguillon, David and Levey, Allan I. and Johnson, Erik C.
                      B and Seyfried, Nicholas T. and Fagan, Anne M. and Mori,
                      Hiroshi and Masters, Colin},
      title        = {{D}ownstream {B}iomarker {E}ffects of {G}antenerumab or
                      {S}olanezumab in {D}ominantly {I}nherited {A}lzheimer
                      {D}isease},
      journal      = {JAMA neurology},
      volume       = {81},
      number       = {6},
      issn         = {2168-6149},
      address      = {Chicago, Ill.},
      publisher    = {American Medical Association},
      reportid     = {DZNE-2024-00567},
      pages        = {582 - 593},
      year         = {2024},
      abstract     = {Importance Effects of antiamyloid agents, targeting either
                      fibrillar or soluble monomeric amyloid peptides, on
                      downstream biomarkers in cerebrospinal fluid (CSF) and
                      plasma are largely unknown in dominantly inherited Alzheimer
                      disease (DIAD).Objective To investigate longitudinal
                      biomarker changes of synaptic dysfunction,
                      neuroinflammation, and neurodegeneration in individuals with
                      DIAD who are receiving antiamyloid treatment.Design,
                      Setting, and Participants From 2012 to 2019, the Dominantly
                      Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study,
                      a double-blind, placebo-controlled, randomized clinical
                      trial, investigated gantenerumab and solanezumab in DIAD.
                      Carriers of gene variants were assigned 3:1 to either drug
                      or placebo. The present analysis was conducted from April to
                      June 2023. DIAN-TU-001 spans 25 study sites in 7 countries.
                      Biofluids and neuroimaging from carriers of DIAD gene
                      variants in the gantenerumab, solanezumab, and placebo
                      groups were analyzed.Interventions In 2016, initial dosing
                      of gantenerumab, 225 mg (subcutaneously every 4 weeks) was
                      increased every 8 weeks up to 1200 mg. In 2017, initial
                      dosing of solanezumab, 400 mg (intravenously every 4 weeks)
                      was increased up to 1600 mg every 4 weeks.Main Outcomes and
                      Measures Longitudinal changes in CSF levels of neurogranin,
                      soluble triggering receptor expressed on myeloid cells 2
                      (sTREM2), chitinase 3–like 1 protein (YKL-40), glial
                      fibrillary acidic protein (GFAP), neurofilament light
                      protein (NfL), and plasma levels of GFAP and NfL.Results Of
                      236 eligible participants screened, 43 were excluded. A
                      total of 142 participants (mean [SD] age, 44 [10] years; 72
                      female $[51\%])$ were included in the study (gantenerumab,
                      52 $[37\%];$ solanezumab, 50 $[35\%];$ placebo, 40
                      $[28\%]).$ Relative to placebo, gantenerumab significantly
                      reduced CSF neurogranin level at year 4 (mean [SD]
                      β = −242.43 [48.04] pg/mL; P < .001); reduced
                      plasma GFAP level at year 1 (mean [SD]
                      β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean
                      [SD] β = −0.03 [0.01] ng/mL; P = .002), and
                      year 4 (mean [SD] β = −0.06 [0.02] ng/mL;
                      P < .001); and increased CSF sTREM2 level at year 2
                      (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and
                      year 4 (mean [SD] β = 1.06 [0.52] ng/mL;
                      P = .04). Solanezumab significantly increased CSF NfL
                      (log) at year 4 (mean [SD] β = 0.14 [0.06];
                      P = .02). Correlation analysis for rates of change found
                      stronger correlations between CSF markers and fluid markers
                      with Pittsburgh compound B positron emission tomography for
                      solanezumab and placebo.Conclusions and Relevance This
                      randomized clinical trial supports the importance of
                      fibrillar amyloid reduction in multiple AD-related processes
                      of neuroinflammation and neurodegeneration in CSF and plasma
                      in DIAD. Additional studies of antiaggregated amyloid
                      therapies in sporadic AD and DIAD are needed to determine
                      the utility of nonamyloid biomarkers in determining disease
                      modification.</br><b>Key Points</b>Question How do
                      antiamyloid agents affect downstream biomarkers of
                      Alzheimer-related pathophysiology regarding their target
                      engagement with either soluble (solanezumab) or fibrillar
                      (gantenerumab) amyloid?Findings This phase 2/3 double-blind,
                      placebo-controlled, randomized clinical trial including 142
                      participants investigated gantenerumab and solanezumab in
                      individuals with gene variants for dominantly inherited
                      Alzheimer disease. Gantenerumab decreased cerebrospinal
                      fluid (CSF) neurogranin and plasma glial fibrillary acidic
                      protein levels while increasing CSF levels of soluble
                      triggering receptor expressed on myeloid cells 2; in
                      contrast, solanezumab treatment was associated with
                      increased CSF neurofilament light protein levels.Meaning
                      Antiamyloid agents removing fibrillar amyloid plaques
                      demonstrated effects on glial and postsynaptic fluid
                      biomarkers downstream of initial amyloid deposition, whereas
                      binding soluble amyloid-β was associated with increased
                      measures of neurodegeneration.},
      cin          = {AG Levin / AG Jucker / Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1111016 / I:(DE-2719)1210001 /
                      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},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38683602},
      doi          = {10.1001/jamaneurol.2024.0991},
      url          = {https://pub.dzne.de/record/269526},
}