Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease

Dominantly Inherited Alzheimer Net, Nelly Joseph-Mathurin, Jorge J. Llibre-Guerra, Yan Li, Austin A. McCullough, Carsten Hofmann, Jakub Wojtowicz, Ethan Park, Guoqiao Wang, Gregory M. Preboske, Qing Wang, Brian A. Gordon, Charles D. Chen, Shaney Flores, Neelum T. Aggarwal, Sarah B. Berman, Thomas D. Bird, Sandra E. Black, Bret Borowski, William S. BrooksJasmeer P. Chhatwal, Roger Clarnette, Carlos Cruchaga, Anne M. Fagan, Martin Farlow, Nick C. Fox, Serge Gauthier, Jason Hassenstab, Diana A. Hobbs, Karen C. Holdridge, Lawrence S. Honig, Russ C. Hornbeck, Ging-Yuek R. Hsiung, Clifford R. Jack, Ivonne Z. Jimenez-Velazquez, Mathias Jucker, Gregory Klein, Johannes Levin, Michele Mancini, Mario Masellis, Nicole S. McKay, Catherine J. Mummery, John M. Ringman, Hiroyuki Shimada, B. Joy Snider, Kazushi Suzuki, David Wallon, Chengjie Xiong, Roy Yaari, Eric McDade, Richard J. Perrin, Randall J. Bateman, Stephen P. Salloway, Tammie L. S. Benzinger, David B. Clifford

Research output: Contribution to journalArticlepeer-review

Abstract

Objective To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). 

Methods 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating (R) (CDR (R)), neuropsychological testing, CSF biomarkers, beta-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. 

Results Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-e4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. 

Interpretation In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-e4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022

Original languageEnglish
Pages (from-to)729-744
Number of pages16
JournalAnnals of Neurology
Volume92
Issue number5
DOIs
Publication statusPublished - Nov 2022

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