Background: Amyloid-plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer disease (AD), however the potential for delaying the onset of clinical symptoms in asymptomatic people are unknown. We conducted a trial of gantenerumab to evaluate whether amyloid-plaque removal delays symptom onset and AD progression in asymptomatic dominantly inherited AD (DIAD) individuals. Methods: This double-blind, phase 2/3 trial, followed by open-label extension (OLE), investigated increasing gantenerumab doses up to 1500 mg subcutaneous every 2 weeks (NCT01760005). We report Interim and Final Analyses of clinical outcomes, amyloid-plaque removal, and biomarkers in asymptomatic mutation carriers treated for up to 10 years. The final primary endpoint was the change from OLE baseline to year 3 in PiB-PET SUVR. Key secondary endpoints were the time to recurrent progression of the Clinical Dementia Rating® (CDR) using the Cox proportional hazards model, compared to internal and external controls. Findings: The primary outcome was positive with amyloid removal of 0.71 SUVR (95% CI 0.53 to 0.88, p< 0.0001). For the clinical decline of CDR-SB, in the group with any gantenerumab exposure (n=53, average dosing 4.3 years), the hazard ratio was 0.79 (0.48 to 1.29), while in the longest-treated group (n=22, average 8.4 years), the hazard ratio was 0.57 (0.31 to 1.07). CSF amyloid-beta 42/40 and p-tau181/tau181 improved proportionally with amyloid reduction. Amyloid-related imaging abnormalities occurred in 53% of participants: 47% with microhemorrhages, 30% with edema, and 6% were associated with symptoms. No treatment-associated macrohemorrhages or deaths occurred. Interpretation: While the overall group did not show significant clinical effects, results suggest potential delayed symptom onset and dementia progression in asymptomatic DIAD individuals with long-term, high-dose gantenerumab exposure. Firm conclusions are limited due to the OLE design and use of external controls. Funding: National Institutes on Aging, Alzheimers Association, GHR, F. Hoffmann-La Roche, Ltd/Genentech

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NCT01760005, IND 115652

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers U01AG042791, U01AG042791-S1 (FNIH and Accelerating Medicines Partnership), R1AG046179, R01AG053267, R01AG053267-S1, R01AG053267-S2. The research for the DIAN-TU-001 gantenerumab open label extension was supported by the Alzheimers Association and F. Hoffman-LaRoche Ltd. The research for the DIAN-TU-001 trial, solanezumab and gantenerumab drug arms, was also supported by the Alzheimers Association, Eli Lilly and Company, F. Hoffman-LaRoche Ltd., Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly and Company), GHR Foundation, an anonymous organization, Cerveau Technologies, Cogstate, and Signant. The DIAN-TU has received funding from the DIAN-TU Pharma Consortium. We acknowledge the altruism of the participants and their families and contributions of the DIAN, DIAN Expanded Registry, and DIAN-TU research and support staff at each of the participating sites (see DIAN-TU Study Team) for their contributions to this study.

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Ethics approval was obtained through a central Institutional Review Board (Advarra) for US sites. Ethics committee approval was obtained at all other participating sites. Country Ethics Committee(s) Reviewed/Approved Australia Bellberry Human Research Ethics Committee Royal Melbourne Hospital Human Research Ethics Committee Canada McGill University Institutional Review Board The University of British Columbia Clinical Research Ethics Board Sunnybrook Health Sciences Centre Research Ethics Board France North-West 1 Ethics Committee Ireland St. Vincent's Healthcare Group Ethics & Medical Research Committee Spain The Drug Research Ethics Committee of the Hospital Clinic of Barcelona UK South Central-Berkshire Research Ethics Committee US/Puerto Rico Advarra Institutional Review Board

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