Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease
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Published:2024-06-01
Issue:6
Volume:81
Page:582
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ISSN:2168-6149
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Container-title:JAMA Neurology
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language:en
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Short-container-title:JAMA Neurol
Author:
Wagemann Olivia12, Liu Haiyan1, Wang Guoqiao3, Shi Xinyu3, Bittner Tobias4, Scelsi Marzia A.5, Farlow Martin R.6, Clifford David B.1, Supnet-Bell Charlene1, Santacruz Anna M.1, Aschenbrenner Andrew J.1, Hassenstab Jason J.1, Benzinger Tammie L. S.7, Gordon Brian A.7, Coalier Kelley A.8, Cruchaga Carlos9, Ibanez Laura19, Perrin Richard J.110, Xiong Chengjie3, Li Yan1, Morris John C.1, Lah James J.11, Berman Sarah B.12, Roberson Erik D.13, van Dyck Christopher H.14, Galasko Douglas15, Gauthier Serge16, Hsiung Ging-Yuek R.17, Brooks William S.1819, Pariente Jérémie20, Mummery Catherine J.21, Day Gregory S.22, Ringman John M.23, Mendez Patricio Chrem24, St. George-Hyslop Peter25, Fox Nick C.21, Suzuki Kazushi26, Okhravi Hamid R.27, Chhatwal Jasmeer28, Levin Johannes22930, Jucker Mathias3132, Sims John R.33, Holdridge Karen C.33, Proctor Nicholas K.33, Yaari Roy33, Andersen Scott W.33, Mancini Michele33, Llibre-Guerra Jorge1, Bateman Randall J.1, McDade Eric1, , Daniels Alisha J.34, Courtney Laura34, Xu Xiong34, Lu Ruijin34, Gremminger Emily34, Franklin Erin34, Ibanez Laura34, Jerome Gina34, Herries Elizabeth34, Stauber Jennifer34, Baker Bryce34, Minton Matthew34, Goate Alison M.34, Renton Alan E.34, Picarello Danielle M.34, Hornbeck Russ34, Chen Allison34, Chen Charles34, Flores Shaney34, Joseph-Mathurin Nelly34, Jarman Steve34, Jackson Kelley34, Keefe Sarah34, Koudelis Deborah34, Massoumzadeh Parinaz34, McCullough Austin34, McKay Nicole34, Nicklaus Joyce34, Pulizos Christine34, Wang Qing34, Sabaredzovic Edita34, Smith Hunter34, Scott Jalen34, Simmons Ashlee34, Rizzo Jacqueline34, Smith Jennifer34, Stout Sarah34, Karch Celeste M.34, Marsh Jacob34, Holtzman David M.34, Barthelemy Nicolas34, Xu Jinbin34, Noble James M.34, Ikonomovic Snezana34, Nadkarni Neelesh K.34, Graff-Radford Neill R.34, Ikeuchi Takeshi34, Kasuga Kensaku34, Niimi Yoshiki34, Huey Edward D.34, Salloway Stephen34, Schofield Peter R.34, Bechara Jacob A.34, Martins Ralph34, Cash David M.34, Ryan Natalie S.34, Laske Christoph34, Hofmann Anna34, Kuder-Buletta Elke34, Graber-Sultan Susanne34, Obermueller Ulrike34, Roedenbeck Yvonne34, Vӧglein Jonathan34, Lee Jae-Hong34, Roh Jee Hoon34, Sanchez-Valle Raquel34, Rosa-Neto Pedro34, Allegri Ricardo F.34, Surace Ezequiel34, Vazquez Silvia34, Lopera Francisco34, Leon Yudy Milena34, Ramirez Laura34, Aguillon David34, Levey Allan I.34, Johnson Erik C.B34, Seyfried Nicholas T.34, Fagan Anne M.34, Mori Hiroshi34, Masters Colin34
Affiliation:
1. Department of Neurology, Washington University School of Medicine, St Louis, Missouri 2. Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany 3. Department of Biostatistics, Washington University in St Louis, St Louis, Missouri 4. F. Hoffmann-La Roche Ltd, Basel, Switzerland 5. F. Hoffmann-La Roche Products Ltd, Welwyn Garden City, United Kingdom 6. Department of Neurology, Indiana University School of Medicine, Indianapolis 7. Department of Radiology, Washington University in St Louis, St Louis, Missouri 8. IQVIA, Durham, North Carolina 9. Department of Psychiatry, Washington University in St Louis, St Louis, Missouri 10. Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri 11. Department of Neurology, School of Medicine Emory University, Atlanta, Georgia 12. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania 13. Department of Neurology, University of Alabama at Birmingham, Birmingham 14. Alzheimer’s Disease Research Unit, Yale School of Medicine, New Haven, Connecticut 15. Department of Neurology, University of California, San Diego 16. Department of Neurology & Psychiatry, McGill University, Montréal, Québec, Canada 17. Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada 18. Neuroscience Research Australia, Sydney, New South Wales, Australia 19. School of Clinical Medicine, University of New South Wales, Randwick, New South Wales, Australia 20. Department of Neurology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France 21. Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom 22. Department of Neurology, Mayo Clinic Florida, Jacksonville 23. Department of Neurology, University of Southern California, Los Angeles 24. Fundación Para la Lucha Contra las Enfermedades Neurológicas de la Infancia (FLENI), Buenos Aires, Argentina 25. Department of Neurology, Columbia University, New York, New York 26. National Defense Medical College, Saitama, Japan 27. Department of Geriatrics, Eastern Virginia Medical School, Norfolk 28. Department of Neurology, Massachusetts General and Brigham & Women’s Hospitals, Harvard Medical School, Boston 29. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany 30. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany 31. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany 32. Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 33. Eli Lilly and Company, Indianapolis, Indiana 34. for the Dominantly Inherited Alzheimer Network–Trials Unit
Abstract
ImportanceEffects 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).ObjectiveTo investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment.Design, Setting, and ParticipantsFrom 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.InterventionsIn 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 MeasuresLongitudinal 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.ResultsOf 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 RelevanceThis 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.Trial RegistrationClinicalTrials.gov Identifier: NCT04623242
Publisher
American Medical Association (AMA)
Cited by
4 articles.
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