Bacillus Calmette‐Guérin (BCG) treatment of bladder cancer protects against Alzheimer’s Disease in older adults: The Massachusetts General Brigham cohort

Abstract

BackgroundRetraining the immune system offers a potential means of preventing or treating Alzheimer’s disease (AD). Vaccines can confer non‐specific beneficial effects (NSBEs), impacting diseases far afield from the original target. The Bacillus Calmette‐Guérin (BCG) vaccine, used worldwide in the prevention of tuberculosis, causes NSBE on non‐TB respiratory infections, type 1 diabetes, and multiple sclerosis. BCG is the gold‐standard therapy for non–muscle‐invasive bladder cancer. Recently, several retrospective studies have associated intravesicular BCG treatment of bladder cancer with lowered risk of AD (Gofrit et al., 2019, Klinger et al., 2021, Kim et al., 2021). We sought to replicate the retrospective study in a large cohort of patients in the Massachusetts General Brigham (MGB) System.MethodWe retrieved 30y of electronic health records from MGB, consisting of 17,920 subjects with new bladder cancer diagnoses. We limited records to patients aged >50y, without a previous dementia diagnosis, and with at least one year MGB follow‐up after diagnosis. Using natural language processing (NLP), we identified and assigned pathological stages to each patient’s first transurethral resection of bladder tumor (TURBT) surgical pathology report. The study population consisted of non‐muscle‐invasive bladder cancer (NMIBC) patients (n = 6467). The intervention group was patients who had any exposure to intravesical BCG, determined by semiautomated methods using NLP and manual validation. The control group was NMIBC patients without exposure to intravesical BCG.ResultWe found a protective effect of BCG on the risk of dementia. Cox analysis of time to AD: HR 0.84, CI (0.7‐0.99), p = 0.049, age and sex‐adjusted. In a stratified analysis by age, the effect of BCG treatment on patients 70 or older was more pronounced (HR 0.77, CI 0.63‐0.95, p = 0.017), whereas there was no effect on patients younger than 70 (HR 0.98, CI 0.72 ‐ 1.36, p = 0.98).ConclusionFindings from our large retrospective study suggest an overall protective effect of BCG treatment on the subsequent incidence of Alzheimer’s Disease, with the effect largely drawing from patients 70yo or older. Further survival and competing risk analyses will be provided to contextualize the basis for these apparently beneficial effects of BCG.