Protocol Version 3.0 Removed the potential to drop a dose between Part 1 and Part 2; thus, the study included 3 AL002 dose arms compared to placebo. Updated the statistical methodology such that proportional mixed-effect models for repeated measures (MMRM) is the primary analysis method, and reestimated the sample size. Updated such that interim analyses were not mandatory. Specified the management of ARIA.

Protocol Version 4.0 A titration period was incorporated such that newly enrolled participants randomized to 40 or 60 mg/kg would be titrated to their assigned dose over 2 or 3 doses, respectively. Additional MRI scans were added for participants in Part 1 which were to be conducted after the first dose, on Study Day 15, and before the second dose. An additional MRI scan was added for participants in Part 2 which was to be conducted after the third dose and before the fourth dose. Additional monitoring guidelines were added for participants with any evidence of ARIA, including recommendations for administration of steroids, as applicable. The option to collect an additional PET and/or LP after an occurrence of ARIA was added. The status of Study AL002-1 and study results were updated. Collection of additional optional blood samples for PK from approximately 24 Part 2 participants added; to be collected at 1 of the following timepoints: Week 25, 37 or 49. Central reads for triplicate electrocardiograms from Day 1 and Weeks 25 or 49 in approximately 100 participants added. Inclusion of criteria for administration of rescue medication for participants who experienced rapid cognitive decline. Statistical methodology updated to be consistent with the latest version of the Statistical Analysis Plan.

Protocol Version 5.0 Additional information added related to ARIA risks and descriptions. Participants with the APOE e4/e4 genotype were no longer eligible for this study; added due to emerging ARIA seen in this patient population. Option for additional unscheduled MRI scans to be requested by the Sponsor for the detection and follow-up of ARIA added. Inclusion/Exclusion criteria updated for clarity, safety, and to facilitate recruitment (specific details are available in the protocol. Statistical methods updated to enhance precision of statistical analyses with revised estimands and associated analytical methods including revisions to sample size calculations, analysis sets, analyses of the primary efficacy endpoint, secondary efficacy endpoints, and interim analysis. Updated to allow participants who consented to the optional Winterlight Labs Speech Assessment (WLSA) to complete the baseline measurement either at the Predose Baseline Visit or prior to dosing on Day 1. Additional optional blood samples for PK to be collected from approximately 64 participants (previously 24) in Part 2 at 4, 8 and 24 (or 48) hours after the end of infusion at Week 25 or 37, or 49. Additional safety surveillance activities added: AEs and special situations related to Neuraceq® to be reported within 24 hours of awareness. In the event of treatment-emergent ARIA, post-randomization MRIs required and study drug dosing to be managed. Clarified that MRIs will be read by a Central Imaging Reader.

Protocol Version 6.0 Exclusion criterion updated for safety (specific details are available in the protocol. Restriction on use of anticoagulant medications updated for safety. For participants who temporarily stop study drug due to ARIA-E/ARIA-H, requirement for MRI after restarting study drug (prior to second postresumption dose) added.

Protocol Version 7.0 Detailed, specific content related to early ARIA cases removed and crossreference to the Investigator’s Brochure maintained to ensure the most recent data are available to investigators. Estimand description for the primary efficacy endpoint updated to include change from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) from Weeks 24, 48, 72, and 96 to Weeks 25, 49, 73, and 97. Number of participants enrolled updated from 264 to 328 and sample size calculations updated to account for the increase. Number of sites updated to ‘approximately 90 sites’. Description related to potential study drug administration in a home setting removed. Clarified that extensions to the screening period may be permitted with approval by the Sponsor for reasons other than Coronavirus disease 2019 (COVID-19) and imaging study-related delays. Inclusion/Exclusion criteria updated for clarity, safety, and to facilitate recruitment (specific details are available in the protocol). Requirement to repeat a positive PrecivityAD™-Aβ blood assessment on rescreening removed. Updated to indicate that signs and symptoms indicative of uveitis should be recorded as adverse events and followed by ophthalmology until they have resolved or uveitis ruled out. Content and references for ARIA-related symptoms and signs added for investigator awareness.