Research progress on Alzheimer's disease vaccines: from Aβ-targeted approaches to clinical translation

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive impairment, with the β-amyloid protein (Aβ) aggregation as a core pathological driver. As global aging intensifies, AD poses a severe public health burden, highlighting the urgency of developing effective immunotherapies. This review aims to systematically summarize the research progress of Aβ-targeted AD vaccines, from first-generation approaches to next-generation strategies, and discuss key challenges and future directions for clinical translation.

A comprehensive literature search was conducted across PubMed, Web of Science, the Cochrane Library, EMBASE, and Google Scholar up to 14 November 2025. Relevant studies were selected using predefined eligibility criteria, focusing on Aβ-targeted AD vaccines' development, mechanisms, preclinical efficacy, and clinical outcomes. Review articles and meta-analyses were included, while case reports and non-Aβ-targeted studies were excluded. Data extraction and synthesis focused on vaccine strategies, immune mechanisms, and translational challenges.

First-generation Aβ vaccine (e.g., AN-1792) showed preclinical promise but failed clinically due to autoimmune complications. Next-generation vaccines, including peptide/epitope vaccines, DNA vaccines, viral vector vaccines, and protein self-assembling vaccines, have been developed to induce protective Th2-biased immune responses while avoiding harmful T-cell reactions. Preclinical studies demonstrate reduced Aβ deposition and improved cognitive function, with several candidates advancing to clinical trials showing favorable safety and immunogenicity. Key mechanisms include Fc receptor-mediated phagocytosis, antibody-mediated fibril disaggregation, and the peripheral Aβ sink effect.

Aβ-targeted AD vaccines have evolved toward safer and more effective designs, with multiple strategies showing translational potential. Challenges remain, including blood-brain barrier (BBB) penetration, immune response modulation, and defining optimal therapeutic time windows. Future research should focus on personalized vaccines, combination therapies, and novel antigen delivery platforms to fully realize the clinical potential of AD immunotherapies.