OBJECTIVE: This study investigated the effect of 0.2 % chlorhexidine gluconate on oral microbiota dysbiosis in Alzheimer's disease (AD) and explored potential links between oral microbiota and cognition, offering new insights into its role in AD treatment. STUDY DESIGN: We assessed the impact of 0.2 % chlorhexidine gluconate on the oral microbiota of patients with AD. One hundred patients were divided into two groups based on oral health score (using a cut-off of 8). Subgingival plaque samples were analyzed using 16S rRNA sequencing; no significant differences in bacterial composition were observed between groups at baseline. RESULTS: Poor oral health correlated with higher oral health scores ( = 0.000), fewer teeth ( = 0.002), lower cognitive levels ( = 0.048), and a higher proportion of patients with diabetes ( = 0.032). After 24 weeks of treatment with 0.2 % chlorhexidine gluconate in a randomized controlled trial, subgingival plaques from 66 patients showed changes in and ( < 0.05). a and were identified as potential interventional targets. CONCLUSION: Chlorhexidine gluconate effectively alters oral flora, reducing harmful bacteria. Targeting specific microbiota disturbances may offer a promising strategy to delay AD onset or slow its progression. TRIAL REGISTRATION: This research was registered with the Chinese Clinical Trial Registry (ChiCTR; Reference: ChiCTR2000032876). Registered: 14th of May 2020; http://www.chictr.org.cn/showprojen.aspx?proj=53555.