Immunotherapeutic Strategies Targeting Amyloid-β and Tau in Alzheimer’s Disease: A Systematic Review of Clinical Efficacy, Safety, and Translational Limitations

Abstract

Alzheimer’s disease (AD) is one of the leading neurodegenerative disorders affecting over 55 million individuals worldwide, with a limited selection of disease-modifying therapies. The amyloid cascade hypothesis proposes that amyloid-beta (Aβ) peptide accumulation initiates a cascade of synaptic dysfunction, neuroinflammation, tau pathology, and progressive neurodegeneration, forming the basis for immunotherapeutic strategies. This systematic review analyzes 17 clinical publications from 14 parent trials of anti-amyloid and anti-tau immunotherapies, retrieved from PubMed on April 26, 2026, including reports about passive monoclonal antibodies and active vaccine approaches, to evaluate their effects on disease progression and key limitations. A second database search of Europe PMC was conducted on July 20, 2026, to identify additional eligible sources, but yielded no viable results. Antiamyloid therapies, particularly lecanemab and donanemab, suggest statistically significant reductions in amyloid burden and cognitive decline in early-stage populations. However, these benefits are modest and are associated with amyloid-related imaging abnormalities (ARIA), occurring more frequently in apolipoprotein E (APOE) ε4 carriers. In contrast, anti-tau immunotherapies, despite achieving target engagement and reductions in cerebrospinal fluid biomarkers, have not demonstrated consistent clinical benefit in randomized trials. Overall, immunotherapy provides evidence showing disease-modifying activity in early AD stages, whereas tau-directed immunotherapy clinical efficacy remains uncertain. However, limitations in efficacy, safety, trial design, and accessibility must be addressed before these approaches can achieve broader impact. The findings in this review should consider current limitations regarding evidence base, use of secondary/post-hoc analyses, and variability in outcomes, and future research should address this.