Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2024 Jun 1;81(6):582-593.
doi: 10.1001/jamaneurol.2024.0991.

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial

Olivia Wagemann  1   2 , Haiyan Liu  1 , Guoqiao Wang  3 , Xinyu Shi  3 , Tobias Bittner  4 , Marzia A Scelsi  5 , Martin R Farlow  6 , David B Clifford  1 , Charlene Supnet-Bell  1 , Anna M Santacruz  1 , Andrew J Aschenbrenner  1 , Jason J Hassenstab  1 , Tammie L S Benzinger  7 , Brian A Gordon  7 , Kelley A Coalier  8 , Carlos Cruchaga  9 , Laura Ibanez  1   9 , Richard J Perrin  1   10 , Chengjie Xiong  3 , Yan Li  1 , John C Morris  1 , James J Lah  11 , Sarah B Berman  12 , Erik D Roberson  13 , Christopher H van Dyck  14 , Douglas Galasko  15 , Serge Gauthier  16 , Ging-Yuek R Hsiung  17 , William S Brooks  18   19 , Jérémie Pariente  20 , Catherine J Mummery  21 , Gregory S Day  22 , John M Ringman  23 , Patricio Chrem Mendez  24 , Peter St George-Hyslop  25 , Nick C Fox  21 , Kazushi Suzuki  26 , Hamid R Okhravi  27 , Jasmeer Chhatwal  28 , Johannes Levin  2   29   30 , Mathias Jucker  31   32 , John R Sims  33 , Karen C Holdridge  33 , Nicholas K Proctor  33 , Roy Yaari  33 , Scott W Andersen  33 , Michele Mancini  33 , Jorge Llibre-Guerra  1 , Randall J Bateman  1 , Eric McDade  1 ; Dominantly Inherited Alzheimer Network–Trials Unit
Collaborators, Affiliations
Randomized Controlled Trial

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial

Olivia Wagemann et al. JAMA Neurol. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bittner reported being employed by and receiving stock options from F. Hoffmann-LaRoche and having a patent for P34813-WO pending outside the submitted work. Dr Scelsi reported being an employee of Roche Products Ltd outside the submitted work. Dr Clifford reported receiving consulting/data safety monitoring fees from Roche, Sanofi, Wave, Seagen, Atara, ICON and CellEvolve and royalties from UpToDate outside the submitted work. Dr Santacruz reported receiving grants from National Institutes on Aging, Alzheimer’s Association, GHR Foundation, and an anonymous donor and having a contractual agreement with Roche during the conduct of the study. Dr Hassenstab reported receiving personal fees from Prothena and AlzPath outside the submitted work. Dr Benzinger reported receiving consultant fees from Eli Lilly, Eisai, and Biogen; receiving grants from Siemens; and having a patent issued for use of diffusion MRI for neuroinflammation. Dr Perrin reported receiving grants from the National Institutes of Health (NIH) outside the submitted work. Dr Xiong reported receiving grants from NIH during the conduct of the study. Dr Lah reported receiving grants from Roche Diagnostics outside the submitted work. Dr Berman reported receiving grants from the National Institute on Aging (NIA) during the conduct of the study. Dr Roberson reported receiving grants from NIH/Washington University; personal fees from Eli Lilly and AGTC; and having a patent for tau reduction issued and for tau mouse model with royalties paid from Genentech. Dr van Dyck reported receiving grants from Washington University in St Louis for multicenter clinical trial; grants from Biogen, Eli Lilly, Janssen, UCB, Roche, Genentech, Eisai, and Cerevel and consulting fees from Roche, Eisai, Ono, and Cerevel outside the submitted work. Dr Galasko reported receiving personal fees from Eisai, Biogen, GE Healthcare, Artery Therapeutics, and Fujirebio outside the submitted work. Dr Gauthier reported receiving grants from the NIA RCT; advisory board/working group fees from Alzheon, AmyriAD, Biogen Canada, Eisai Canada, Karuna, Otsuka Canada, Novo Nordisk Canada, and TauRx Chair; and being an editorial board member of JPAD and The Neurotorium. Dr Hsiung reported receiving grants from Anavax, Biogen, CIHR, NIA/NIH; advisory board fees from Biogen, Eli Lilly, and Novo Nordisk; and being the current president of the Consortium of Canadian Centers for Clinical Cognitive Research. Dr Pariente reported receiving personal fees from Biogen outside the submitted work. Dr Mummery reported receiving grants from Biogen and personal fees from Biogen, Eisai, Eli Lilly, Alector, and Roche outside the submitted work. Dr Day reported receiving grants from NIH/NIA and research support from AVID Radiopharmaceuticals outside the submitted work. Dr Ringman reported receiving personal fees from Eisai Pharmaceuticals and grants from Avid Pharmaceuticals outside the submitted work. Dr Fox reported receiving personal fees from Roche/Genentech, Biogen, Eli Lilly, Eisai, and Siemens, and nonfinancial support from Ionis outside the submitted work. Dr Chhatwal reported receiving grants from the NIH during the conduct of the study. Dr Levin reported receiving grants from DZNE during the conduct of the study; personal/speaker/consulting fees from Bayer Vital, Biogen, Eisai, Teva, Zambon, Merck, Roche, Axon Neuroscience, Thieme medical publishers, W. Kohlhammer GmbH, and Modag GmbH, and having a patent for Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies pending. Drs Sims, Holdridge, Proctor, Yaari, Andersen, and Mancini reported being employees and shareholders of Eli Lilly during the conduct of the study. Dr Bateman reported receiving laboratory research funding from the National Institutes of Health, Alzheimer’s Association, BrightFocus Foundation, Rainwater Foundation, Association for Frontotemporal Degeneration FTD Biomarkers Initiative, Avid Radiopharmaceuticals, Janssen, Tau Consortium, Novartis, Centene Corporation, Association for Frontotemporal Degeneration, the Cure Alzheimer’s Fund, Coins for Alzheimer’s Research Trust Fund, The Foundation for Barnes-Jewish Hospital, Good Ventures Foundation, DIAN-TU Pharma Consortium, Tau SILK Consortium (AbbVie, Biogen, Eli Lilly, and an anonymous organization), the NfL Consortium (AbbVie, Biogen, Bristol Myers Squibb, Hoffman–La Roche), and the Tracy Family SILQ Center; having equity ownership interest in C2N Diagnostics and receiving income based on technology licensed by Washington University to C2N Diagnostics; and receiving income from C2N Diagnostics for serving on the scientific advisory board. Dr McDade reported receiving grants from Eli Lilly, Hoffmann-LaRoche, NIA, and Alzheimer Association; and advisory board fees from Eli Lilly, Hoffman-LaRoche, Alector, Alzamend, Merck, Sanofi, and Sage outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Estimated Mean Change From Baseline for Gantenerumab, Solanezumab, and Placebo for Cerebrospinal Fluid (CSF) Markers
Assessment of CSF markers was done for both gantenerumab and solanezumab, respectively, in neurogranin (A and B), soluble triggering receptor expressed on myeloid cells 2 (sTREM2; C and D), chitinase 3–like protein 1 (YKL-40; E and F), and glial fibrillary acidic protein (GFAP; G and H),
Figure 2.
Figure 2.. Estimated Mean Change From Baseline for Gantenerumab, Solanezumab, and Placebo for Cerebrospinal Fluid (CSF) and Plasma Markers
Assessment of CSF markers was done for both gantenerumab and solanezumab, respectively, in neurofilament light protein (NfL; A and B) and of plasma markers in glial fibrillary acidic protein (GFAP; C and D) and NfL (E and F). All estimations are shown with 95% CI error bars. aResembles a significance of a P value <.05 or lower (Table 2).
Figure 3.
Figure 3.. Correlations for Individual Rate of Change of Cerebrospinal Fluid (CSF) and Plasma Markers and Tests
CSF biomarkers included neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma markers included GFAP and NfL. Tests included Pittsburgh compound B (PiB) positron emission tomography (PET), [18F]-fluorodeoxyglucose (FDG) PET for precuneus, magnetic resonance imaging (MRI) precuneus thickness. Clinical status was assessed by Clinical Dementia Rating (CDR) sums of boxes (CDRS). The heatmap for the placebo group can be found in eFigure 3 in Supplement 3. NS indicates not significant. YKL-40 indicates chitinase 3–like 1 protein. aP <.05. bP <.01. cP <.001.
See this image and copyright information in PMC

Comment on

References

    1. Jack CR Jr, Knopman DS, Jagust WJ, et al. . Tracking pathophysiological processes in Alzheimer disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207-216. doi:10.1016/S1474-4422(12)70291-0 - DOI - PMC - PubMed
    1. Bateman RJ, Xiong C, Benzinger TLS, et al. ; Dominantly Inherited Alzheimer Network . Clinical and biomarker changes in dominantly inherited Alzheimer disease. N Engl J Med. 2012;367(9):795-804. doi:10.1056/NEJMoa1202753 - DOI - PMC - PubMed
    1. McDade E, Wang G, Gordon BA, et al. ; Dominantly Inherited Alzheimer Network . Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology. 2018;91(14):e1295-e1306. doi:10.1212/WNL.0000000000006277 - DOI - PMC - PubMed
    1. Ryman DC, Acosta-Baena N, Aisen PS, et al. ; Dominantly Inherited Alzheimer Network . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014;83(3):253-260. doi:10.1212/WNL.0000000000000596 - DOI - PMC - PubMed
    1. Bohrmann B, Baumann K, Benz J, et al. . Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis. 2012;28(1):49-69. doi:10.3233/JAD-2011-110977 - DOI - PubMed

MeSH terms

Associated data