The potential role of vaccinations in preventing Alzheimer’s disease (AD) has garnered increasing attention, given the established link between systemic infections, neuroinflammation, and genetic predisposition. In this systematic review, we investigate the function of genetic predisposition in altering the effectiveness of the pneumococcal vaccination in lowering the risk of AD. 

Following PRISMA guidelines, we conducted an extensive search across PubMed, Embase, Web of Science, and Scopus databases from their inception to January 2025. We included studies that investigated the risk of AD in adults aged 65 years and above in relation to pneumococcal vaccination. The quality of the studies was assessed using the Newcastle Ottawa Scale (NOS).

Five high-quality studies (NOS score: 9) were identified. The studies consistently demonstrated a protective effect of the pneumococcal vaccination against AD, with risk reductions ranging from 27% to 63%. Notably, genetic analyses revealed enhanced protective effects among carriers of the rs6859 A allele in the NECTIN2 gene. This indicates that individuals with specific genetic predispositions may benefit more from the vaccine. Comparative analyses also suggested stronger protective associations for the pneumococcal vaccination compared to the influenza vaccination.

This systematic review provides considerable evidence supporting a link between pneumococcal vaccination and reduced AD risk. Significantly, the findings imply that the vaccine’s protective effect is influenced by genetic factors, highlighting the potential advantages of personalized vaccination strategies tailored to an individual’s genetic profile. These insights bear significant implications for public health strategies directed at mitigating the AD burden, especially among genetically vulnerable populations. Future research should concentrate on unveiling the biological mechanisms underpinning this interaction and investigating the incorporation of vaccination into comprehensive dementia prevention programs.