Vaccination is an essential strategy against COVID-19 in the current era of emerging variants. This study evaluates the immunogenicity of the recombinant subunit COVID-19 vaccine (Zifivax) in Alzheimer's disease (AD) patients. A total of 249 patients with Alzheimer's disease (AD) were enrolled in an eight-month, prospective study conducted across three medical centers in Hangzhou, Zhejiang Province, from May 2022 to January 2023, Zhe Jiang province, and were categorized into unvaccinated (AD-UV) and vaccinated groups (AD-V). Levels of RBD-IgG, neutralization antibody activity, and cytokines were identified to evaluate the immune responses. Clinical outcomes were assessed within one month following breakthrough infection (BTI) with the Omicron variant. Following three doses, the vaccine induced a robust immune response, elevating neutralizing antibodies and activating T-cells in AD-V cohort. AD-V patients exhibited significantly higher humoral immune responses compared to AD-UV counterparts. The anti-RBD antibodies level and pseudoviral neutralizing activity demonstrated an increase concurrent with the onset of immunity and infection, and the seroresponse rate exhibited a similar trend in AD-V cohort. RBD-IgG antibody levels against WT, DELTA, and BA.5 variants in AD-V cohort showed significantly higher compared to AD-UV cohort. Following Omicron infection, unvaccinated patients experienced higher levels of Th1/Th2-type cytokines than vaccinated individuals. Vaccination correlated with reduced severe illness, increased survival rates and extended survival times after Omicron BTI. The findings highlight the immunogenicity and suggest a certain degree of protective effectiveness of the recombinant subunit COVID-19 vaccine (Zifivax) in AD patients.