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Bladder Cancer Immunotherapy by BCG is associated with a significantly reduced risk of Alzheimer disease

IMPORTANCE Despite years of investigation and billions of dollars, there is no cure or even a disease-slowing remedy for Alzheimer disease (AD). Most studies thus far have focused on amyloid beta plaques and neurofibrillary tangles as therapeutic targets, and only a few on modulating the associated inflammatory process. OBJECTIVE To determine if exposure to Bacillus Calmette Guerin (BCG) during treatment of non-muscle-invasive bladder cancer (NMIBC) is associated with a lower risk of developing AD. DESIGN, SETTING AND PARTICIPANTS Multicenter retrospective study of 12,185 bladder cancer patients including 2301 BCG treated patients between 2000 and 2019 meeting all inclusion criteria. Data was retrieved from two tertiary hospital systems in Israel and the United States, and the largest Israeli health provider database, with a median follow up of 3.5 to 7 years. MAIN OUTCOMES AND MEASURES The primary outcome was time to the first occurrence of AD/Dementia events following a diagnosis of bladder cancer by trans-urethral resection (TURBT) in BCG treated patients, and in bladder cancer patients not receiving BCG (control group). RESULTS BCG treatment was associated with a significantly reduced risk of developing AD in bladder cancer patients older than 75 years following BCG treatment. A competing risk model using Cox Proportional-Hazard (PH) analysis applied to the largest medical records data showed a Hazard Ratio (HR) of 0.726 (95% CI: 0.529 to 0.996, P = 0.0473). The results were duplicated in analyzing NMIBC patients from a tertiary hospital with a HR of 0.416 (95% CI: 0.203 to 0.853, P = 0.017). A reduction in the risk (by 28%) for developing Parkinson disease (PD) was also shown in bladder cancer patients subjected to BCG immunotherapy. CONCLUSIONS AND RELEVANCE BCG treatment for bladder cancer patients was associated with a significantly reduced risk for developing AD and PD in the elderly population (>75 years), and in NMIBC patients from a tertiary hospital. Prospective studies in elderly inoculated with intradermic BCG should be initiated to evaluate the potential protective effect of BCG against AD and PD.