<h3>Objective:</h3> GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27-month, global, Phase III, randomized, placebo-controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia). <h3>Background:</h3> Gantenerumab is a subcutaneous fully-human monoclonal antibody that binds to aggregated amyloid-beta species, including oligomers, fibrils, and plaques. <h3>Design/Methods:</h3> Eligible participants (50–90 years) with early AD were randomized 1:1 to receive subcutaneous gantenerumab or placebo, administered at the study site or at home. A universal titration scheme for all participants receiving gantenerumab, irrespective of apolipoprotein E ɛ4 (APOEɛ4) genotype, allowed participants to reach a target dose of 510 mg gantenerumab every 2 weeks. This titration maximizes gantenerumab exposure while balancing amyloid removal and amyloid-related imaging abnormalities (ARIA) risk for all individuals. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR-SB; higher scores indicate greater impairment). Secondary confirmatory and exploratory efficacy endpoints, tau and amyloid positron emission tomography, cerebrospinal fluid and plasma biomarkers, were also assessed. <h3>Results:</h3> GRADUATE I and II enrolled 985 and 980 participants, respectively. Change from baseline in CDR-SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference −0.31; 95% CI −0.66 to 0.05) and 2.82 and 3.01 in GRADUATE II (difference −0.19; 95% CI −0.55 to 0.17). The difference between gantenerumab and placebo groups in amyloid reduction at Week 116 was −66.57 (standard error [SE] 4.13) centiloids for GRADUATE I and −56.52 (SE 3.96) centiloids for GRADUATE II. ARIA-edema (ARIA-E) occurred with gantenerumab; ARIA-E were manageable and mostly asymptomatic. <h3>Conclusions:</h3> Gantenerumab did not slow decline in participants with early AD. Clinical benefit may require sufficient amyloid plaque removal; however, the parameters remain to be defined. <b>Disclosure:</b> Dr. Smith has received personal compensation for serving as an employee of Roche Products Ltd. Dr. Smith has stock in Hoffman La Roche. An immediate family member of Prof. Donohue has received personal compensation for serving as an employee of Janssen. Prof. Donohue has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Prof. Donohue has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. An immediate family member of Prof. Donohue has stock in Janssen. The institution of Prof. Donohue has received research support from NIH. Dr. Gruendl has received personal compensation for serving as an employee of F. Hoffmann-La Roche AG. Dr. Gruendl has stock in F. Hoffmann-La Roche AG. Dr. Grimmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AbbVie, Alector, Anavex, Biogen, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche Pharma, UCB, and Vivoryon. Dr. Grimmer has received personal compensation in the range of $500-$4,999 for serving as a lecturer with Grifols, Medical Tribune, Novo Nordisk, Roche Pharma, and Schwabe. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Perry has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen. Dr. Perry has received personal compensation in the range of $0-$499 for serving as a Consultant for Eli Lilly. Dr. Perry has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Black has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. Dr. Black has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Black has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann-La Roche. Dr. Black has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Black has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Black has received research support from Hoffmann-La Roche. The institution of Dr. Black has received research support from Biogen. The institution of Dr. Black has received research support from GE Healthcare. The institution of Dr. Black has received research support from Eli Lilly. The institution of Dr. Black has received research support from Genentech. The institution of Dr. Black has received research support from NovoNordisk. The institution of Dr. Black has received research support from UCB Biopharma. The institution of Dr. Black has received research support from Alkahest Inc. The institution of Dr. Black has received research support from University of Southern California - AHEAD 3-45 Study. Dr. Salloway has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EISAI. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lilly. Dr. Salloway has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for NovoNordisk. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Prothena. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. Dr. Salloway has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bolden. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acumen. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Marco Lyons has nothing to disclose. Dr. Rutten-Jacobs has received personal compensation for serving as an employee of F.Hoffmann-La Roche Ltd.. Dr. Rutten-Jacobs has stock in F.Hoffmann-La Roche Ltd.. Tobias Bittner has received personal compensation for serving as an employee of F.Hoffmann-LaRoche. Tobias Bittner has stock in F.Hoffmann-LaRoche. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen, Axon, JOMDD, Roche, Siemens. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis, Julius Clinical. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for MagQu. Mr. Pelentrides has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Frederik Barkhof has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Combinostics. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for IXICO. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Matteo Tonietto has received personal compensation for serving as an employee of Roche. Matteo Tonietto has stock in Roche. Monika Baudler has received personal compensation for serving as an employee of Roche. Monika Baudler has stock in Roche. Dr. Fontoura has received personal compensation for serving as an employee of F. Hoffmann La Roche. Dr. Fontoura has received stock or an ownership interest from Roche Pharmaceuticals. Rachelle Doody has nothing to disclose.