<jats:sec> <jats:title>Introduction:</jats:title> <jats:p>Alzheimer disease (AD) is a common neurodegenerative disease, and immunomodulation offers treatment opportunities. Preclinical data suggest that intravesical Bacillus Calmette-Guerin (BCG) treatment could delay AD development. We investigated this relationship in a population-based cancer database.</jats:p> </jats:sec> <jats:sec> <jats:title>Sample and Methods:</jats:title> <jats:p>We queried the Surveillance, Epidemiology, and End Results-Medicare database for patients with high-risk nonmuscle-invasive bladder cancer (hrNMIBC). BCG dosage and subsequent Alzheimer diagnosis were collected through ICD-9/10 codes. Multivariable Cox regression was performed to assess the association between BCG therapy and subsequent Alzheimer diagnosis.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>We identified 26,584 hrNMIBC patients; 51% received BCG and 8.3% were diagnosed with Alzheimer. BCG exposure was significantly associated with lower Alzheimer occurrence (hazard ratio: 0.73, <jats:italic toggle="yes">P</jats:italic><0.05), which was dose-dependent. Increasing age, female sex, Black race, and increasing comorbidity index were significantly associated with a greater risk of subsequent Alzheimer diagnosis.</jats:p> </jats:sec> <jats:sec> <jats:title>Discussion:</jats:title> <jats:p>Treatment with intravesical BCG among patients with hrNMIBC was associated with a significantly lower risk for subsequent Alzheimer diagnosis, which seemed dose-dependent.</jats:p> </jats:sec>