Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease
Authors: Wagemann Olivia , Liu Haiyan , Wang Guoqiao , Shi Xinyu , Bittner Tobias , Scelsi Marzia A. , Farlow Martin R. , Clifford David B. , Supnet-Bell Charlene , Santacruz Anna M. , Aschenbrenner Andrew J. , Hassenstab Jason J. , Benzinger Tammie L. S. , Gordon Brian A. , Coalier Kelley A. , Cruchaga Carlos , Ibanez Laura , Perrin Richard J. , Xiong Chengjie , Li Yan , Morris John C. , Lah James J. , Berman Sarah B. , Roberson Erik D. , van Dyck Christopher H. , Galasko Douglas , Gauthier Serge , Hsiung Ging-Yuek R. , Brooks William S. , Pariente Jérémie , Mummery Catherine J. , Day Gregory S. , Ringman John M. , Mendez Patricio Chrem , St. George-Hyslop Peter , Fox Nick C. , Suzuki Kazushi , Okhravi Hamid R. , Chhatwal Jasmeer , Levin Johannes , Jucker Mathias , Sims John R. , Holdridge Karen C. , Proctor Nicholas K. , Yaari Roy , Andersen Scott W. , Mancini Michele , Llibre-Guerra Jorge , Bateman Randall J. , McDade Eric ,   Dominantly Inherited Alzheimer Network–Trials Unit, Daniels Alisha J. , Courtney Laura , Xu Xiong , Lu Ruijin , Gremminger Emily , Franklin Erin , Ibanez Laura , Jerome Gina , Herries Elizabeth , Stauber Jennifer , Baker Bryce , Minton Matthew , Goate Alison M. , Renton Alan E. , Picarello Danielle M. , Hornbeck Russ , Chen Allison , Chen Charles , Flores Shaney , Joseph-Mathurin Nelly , Jarman Steve , Jackson Kelley , Keefe Sarah , Koudelis Deborah , Massoumzadeh Parinaz , McCullough Austin , McKay Nicole , Nicklaus Joyce , Pulizos Christine , Wang Qing , Sabaredzovic Edita , Smith Hunter , Scott Jalen , Simmons Ashlee , Rizzo Jacqueline , Smith Jennifer , Stout Sarah , Karch Celeste M. , Marsh Jacob , Holtzman David M. , Barthelemy Nicolas , Xu Jinbin , Noble James M. , Ikonomovic Snezana , Nadkarni Neelesh K. , Graff-Radford Neill R. , Ikeuchi Takeshi , Kasuga Kensaku , Niimi Yoshiki , Huey Edward D. , Salloway Stephen , Schofield Peter R. , Bechara Jacob A. , Martins Ralph , Cash David M. , Ryan Natalie S. , Laske Christoph , Hofmann Anna , Kuder-Buletta Elke , Graber-Sultan Susanne , Obermueller Ulrike , Roedenbeck Yvonne , Vӧglein Jonathan , Lee Jae-Hong , Roh Jee Hoon , Sanchez-Valle Raquel , Rosa-Neto Pedro , Allegri Ricardo F. , Surace Ezequiel , Vazquez Silvia , Lopera Francisco , Leon Yudy Milena , Ramirez Laura , Aguillon David , Levey Allan I. , Johnson Erik C.B , Seyfried Nicholas T. , Fagan Anne M. , Mori Hiroshi , Masters Colin 
Published: April 2024

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 &amp;lt; .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 &amp;lt; .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