The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia.—A Swedish nationwide cohort study from 1997 to 2019

Abstract

Background Alzheimer’s disease (AD) affects 50 million people worldwide. The immune system plays a major role in the pathogenesis of AD. Several retrospective analyses have reported a decreased risk of AD and other dementias in bladder cancer patients treated with immunotherapy in the form of Bacillus Calmette-Guerin (BCG) bladder instillations. We tested this hypothesis in a Swedish population-based prospective cohort of patients with non-muscle invasive bladder cancer (NMIBC). Methods and findings We utilized the BladderBaSe 2.0 database, which contains tumor-specific, health-related, and socio-demographic information for patients diagnosed with NMIBC between 1997 and 2019. The database also includes a matched comparison cohort sampled from the general population, consisting of individuals free from urinary tract cancer at the time of the index case’s diagnosis. Five controls were randomly selected for each index case without replacement on the date of the index case’s diagnosis. Our inclusion criteria identified participants diagnosed with NMIBC who had received BCG as primary treatment, along with their corresponding comparison cohort. We excluded those diagnosed with dementia before or within 6 months of NMIBC diagnosis. To compare the NMIBC cohort with their matched comparison cohort, we used a stratified Cox model, treating each case with its controls as a stratum. We identified 38,934 patients in the NMIBC cohort, with 6,496 receiving BCG after primary diagnosis (cases). AD/dementia was diagnosed during follow-up in 6.1% of cases and 7.4% of controls. Cases had a slightly lower risk of dementia than controls, with a hazard ratio (HR) of 0.88 (95% confidence interval [CI] 0.780–0.991), and a HR of 0.89 (CI 0.703–1.119) for AD. Subgroup analysis for dementia showed that age over 75 years had an HR of 0.73 (CI 0.616–0.863), and female gender had an HR of 0.73 (CI 0.552–0.971). The associations were similar for AD specifically, but not statistically significant. Similar to previous studies, we analyzed bladder cancer patients treated with and without BCG therapy. Multivariate Cox analysis indicated that those treated with BCG had a lower risk of dementia (HR 0.81, 95% CI 0.71–0.92), and an HR of 0.98 (95% CI 0.75–1.27) for AD specifically. High age was a significant risk modifier; the HR was 3.8 (CI 3.44–4.11) for dementia and 3.1 (CI 2.59–3.73) for AD. Even patients not receiving BCG had a significantly lower risk for AD than controls (HR 0.86, CI 0.77–0.96). Conclusions This study observed a marginally decreased risk of developing AD/dementia associated with earlier intravesical BCG treatment in NMIBC patients. This small benefit was most pronounced in those with high age and female gender. The disparity from previous highly positive studies underscores the importance of using an appropriate control cohort.