Clinical Benefits and Risks of Anti-Amyloid Antibodies in Sporadic Alzheimer’s Disease: Systematic Review and Network Meta-Analysis with Web Application (Preprint)

Despite the increasing approval of antiamyloid antibodies for Alzheimer disease (AD), their clinical relevance and risk-benefit profile remain uncertain. The heterogeneity of AD and the limited availability of long-term clinical data make it difficult to establish a clear rationale for selecting one treatment over another. The aim of this work was to assess and compare the efficacy and safety of antiamyloid antibodies through an interactive online meta-analytic approach by performing conventional pair-wise meta-analyses and frequentist and Bayesian network meta-analyses of phase II and III clinical trial results. To achieve this, we developed AlzMeta.app 2.0, a freely accessible web application that enables researchers and clinicians to evaluate the relative and absolute risks and benefits of these therapies in real time, incorporating different prior choices and assumptions of baseline risks of disease progression and adverse events. We adhered to PRISMA-NMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for reporting of systematic reviews with network meta-analysis) and GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) guidelines for reporting and rating the certainty of evidence. Clinical trial reports (until September 30, 2024) were retrieved from PubMed, Google Scholar, and clinical trial databases (including ClinicalTrials.gov). Studies with <20 sporadic AD patients and a modified Jadad score <3 were excluded. Risk of bias was assessed with the RoB-2 tool. Relative risks and benefits have been expressed as risk ratios and standardized mean differences, with confidence, credible, and prediction intervals calculated for all outcomes. For significant results, the intervention effects were ranked in frequentist and Bayesian frameworks, and their clinical relevance was determined by the absolute risk per 1000 people and number needed to treat (NNT) for a wide range of control responses. Among 7 treatments tested in 21,236 patients (26 studies with low risk of bias or with some concerns), donanemab was the best-ranked treatment on cognitive and functional measures, and it was almost 2 times more effective than aducanumab and lecanemab and significantly more beneficial than other treatments on the global (cognitive and functional) Clinical Dementia Rating Scale-Sum of Boxes (NNT=10, 95% CI 8-16). Special caution is required regarding cerebral edema and microbleeding due to the clinically relevant risks of edema for donanemab (NNT=8, 95% CI 5-16), aducanumab (NNT=10, 95% CI 6-17), and lecanemab (NNT=14, 95% CI 7-31), which may outweigh the benefits. Our results showed that donanemab is more effective and has a safety profile similar to aducanumab and lecanemab, highlighting the need for treatment options with improved safety. Potential bias may have been introduced in the included trials due to unblinding caused by frequent cerebral edema and microbleeds, as well as the impact of the COVID-19 pandemic.