학술논문
Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.
Document Type
Academic Journal
Author
Wagemann O; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.; Liu H; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Wang G; Department of Biostatistics, Washington University in St Louis, St Louis, Missouri.; Shi X; Department of Biostatistics, Washington University in St Louis, St Louis, Missouri.; Bittner T; F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Scelsi MA; F. Hoffmann-La Roche Products Ltd, Welwyn Garden City, United Kingdom.; Farlow MR; Department of Neurology, Indiana University School of Medicine, Indianapolis.; Clifford DB; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Supnet-Bell C; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Santacruz AM; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Aschenbrenner AJ; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Hassenstab JJ; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Benzinger TLS; Department of Radiology, Washington University in St Louis, St Louis, Missouri.; Gordon BA; Department of Radiology, Washington University in St Louis, St Louis, Missouri.; Coalier KA; IQVIA, Durham, North Carolina.; Cruchaga C; Department of Psychiatry, Washington University in St Louis, St Louis, Missouri.; Ibanez L; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Department of Psychiatry, Washington University in St Louis, St Louis, Missouri.; Perrin RJ; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri.; Xiong C; Department of Biostatistics, Washington University in St Louis, St Louis, Missouri.; Li Y; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Morris JC; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Lah JJ; Department of Neurology, School of Medicine Emory University, Atlanta, Georgia.; Berman SB; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.; Roberson ED; Department of Neurology, University of Alabama at Birmingham, Birmingham.; van Dyck CH; Alzheimer's Disease Research Unit, Yale School of Medicine, New Haven, Connecticut.; Galasko D; Department of Neurology, University of California, San Diego.; Gauthier S; Department of Neurology & Psychiatry, McGill University, Montréal, Québec, Canada.; Hsiung GR; Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.; Brooks WS; Neuroscience Research Australia, Sydney, New South Wales, Australia.; School of Clinical Medicine, University of New South Wales, Randwick, New South Wales, Australia.; Pariente J; Department of Neurology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.; Mummery CJ; Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom.; Day GS; Department of Neurology, Mayo Clinic Florida, Jacksonville.; Ringman JM; Department of Neurology, University of Southern California, Los Angeles.; Mendez PC; Fundación Para la Lucha Contra las Enfermedades Neurológicas de la Infancia (FLENI), Buenos Aires, Argentina.; St George-Hyslop P; Department of Neurology, Columbia University, New York, New York.; Fox NC; Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom.; Suzuki K; National Defense Medical College, Saitama, Japan.; Okhravi HR; Department of Geriatrics, Eastern Virginia Medical School, Norfolk.; Chhatwal J; Department of Neurology, Massachusetts General and Brigham & Women's Hospitals, Harvard Medical School, Boston.; Levin J; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Jucker M; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; Sims JR; Eli Lilly and Company, Indianapolis, Indiana.; Holdridge KC; Eli Lilly and Company, Indianapolis, Indiana.; Proctor NK; Eli Lilly and Company, Indianapolis, Indiana.; Yaari R; Eli Lilly and Company, Indianapolis, Indiana.; Andersen SW; Eli Lilly and Company, Indianapolis, Indiana.; Mancini M; Eli Lilly and Company, Indianapolis, Indiana.; Llibre-Guerra J; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; Bateman RJ; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.; McDade E; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
Source
Publisher: American Medical Association Country of Publication: United States NLM ID: 101589536 Publication Model: Print Cited Medium: Internet ISSN: 2168-6157 (Electronic) Linking ISSN: 21686149 NLM ISO Abbreviation: JAMA Neurol Subsets: MEDLINE
Subject
Language
English
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.
Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.
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.
Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.