Passive immunotherapy in Alzheimer’s disease: biomarkers, biological staging, and emerging therapeutic strategies

Abstract Alzheimer’s disease (AD) is increasingly defined and staged using biological markers rather than clinical phenotype alone, reflecting a major shift toward biomarker-based diagnosis and therapeutic stratification. In parallel, passive immunotherapies targeting amyloid-beta (Aβ) and tau have introduced a new disease-modifying direction, particularly in biomarker-confirmed early-stage disease. This review examines the biological framework of AD most relevant to passive immunotherapy, with emphasis on imaging and fluid biomarkers, emerging blood-based diagnostics, and their roles in diagnosis, biological staging, patient selection, and treatment monitoring. We discuss the major anti-amyloid and tau-directed monoclonal antibodies, focusing on their molecular targets, mechanisms of action, clinical trial outcomes, biomarker effects, and safety profiles, including amyloid-related imaging abnormalities (ARIA). Particular attention is given to the evolving role of plasma biomarkers, especially p-tau217 and related ratios, in supporting earlier biological confirmation and more accessible therapeutic stratification. We also compare amyloid- and tau-directed strategies, highlighting the greater clinical maturity and regulatory advancement of amyloid-targeting therapies, alongside the stronger pathological association of tau with neurodegeneration and cognitive decline but the greater translational challenges facing tau-based approaches. In addition, the review discusses the growing importance of biomarker-guided treatment frameworks and the practical challenges of implementing these strategies in resource-limited healthcare settings. Overall, passive immunotherapy represents an important step toward biologically guided treatment in AD; however, its long-term clinical impact will likely depend on earlier intervention, improved patient stratification, broader biomarker accessibility, and the development of stage-specific and potentially combination-based therapeutic approaches.