Intravesical Bacillus Calmette-Guérin Treatment Is Inversely Associated With the Risk of Developing Alzheimer Disease or Other Dementia Among Patients With Non–muscle-invasive Bladder Cancer

Kim, Joseph I.; Zhu, Denzel; Barry, Emily; Kovac, Evan; Aboumohamed, Ahmed; Agalliu, Ilir; Sankin, Alex

doi:10.1016/j.clgc.2021.05.001

Cited by 21 publications

(33 citation statements)

References 27 publications

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“…Another mechanism related to innate immunity that potentially underlies the association between flu vaccination and AD is alteration of the sustained low-grade systemic elevation of proinflammatory cytokines referred to as "inflammaging" that is commonly observed among older adults [51]. Regardless of the exact mechanism, the relevance of innate immune training is supported by the growing literature that other adulthood vaccines (including those for tetanus and diphtheria, zoster, and tuberculosis) are associated with reduced dementia risk [6,[11][12][13][14][15][16][17][18][19][20][21]. Of particular interest are studies from the US and Israel that found a lower risk of AD in patients with bladder cancer who had received intravesical immunotherapy with BCG, a vaccine for tuberculosis, compared to those who had not undergone BCG immunotherapy [14,15].…”

Section: Hypothesized Mechanism(s)mentioning

confidence: 99%

“…Regardless of the exact mechanism, the relevance of innate immune training is supported by the growing literature that other adulthood vaccines (including those for tetanus and diphtheria, zoster, and tuberculosis) are associated with reduced dementia risk [6,[11][12][13][14][15][16][17][18][19][20][21]. Of particular interest are studies from the US and Israel that found a lower risk of AD in patients with bladder cancer who had received intravesical immunotherapy with BCG, a vaccine for tuberculosis, compared to those who had not undergone BCG immunotherapy [14,15]. Because the prevalence of tuberculosis is low in the US [52], the association of BCG exposure with lowered dementia risk argues against an avoidance-of-infection mechanism and instead supports a non-microbe-specific mechanism such as trained immunity.…”

Section: Hypothesized Mechanism(s)mentioning

confidence: 99%

“…Prevention or attenuation of microbe-related inflammation may therefore represent a rational strategy to delay or reduce the risk of neurodegenerative disease. Consistent with this hypothesis, studies have found a decreased risk of dementia associated with prior exposure to various adulthood vaccinations, including those for tetanus, diphtheria, pertussis (Tdap) [11][12][13]; poliomyelitis [11]; tuberculosis [14,15]; herpes zoster (i.e., shingles) [6,13,16,17]; and influenza [11,[18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Risk of Alzheimer’s Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching

Bukhbinder

Ling

Hasan³

et al. 2022

JAD

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Background: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including Veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer’s disease (AD) risk in a general cohort of older US adults has not been characterized. Objective: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database. Methods: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years old by the start of follow-up. Propensity-score matching (PSM) was used to create flu-vaccinated and flu-unvaccinated cohorts with similar baseline demographics, medication usage, and comorbidities. Relative risk (RR) and absolute risk reduction (ARR) were estimated to assess the effect of influenza vaccination on AD risk during the 4-year follow-up. Results: From the unmatched sample of eligible patients (n = 2,356,479), PSM produced a sample of 935,887 flu–vaccinated-unvaccinated matched pairs. The matched sample was 73.7 (SD, 8.7) years of age and 56.9% female, with median follow-up of 46 (IQR, 29–48) months; 5.1% (n = 47,889) of the flu-vaccinated patients and 8.5% (n = 79,630) of the flu-unvaccinated patients developed AD during follow-up. The RR was 0.60 (95% CI, 0.59–0.61) and ARR was 0.034 (95% CI, 0.033–0.035), corresponding to a number needed to treat of 29.4. Conclusion: This study demonstrates that influenza vaccination is associated with reduced AD risk in a nationwide sample of US adults aged 65 and older.

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Section: Hypothesized Mechanism(s)mentioning

confidence: 99%

Section: Hypothesized Mechanism(s)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Risk of Alzheimer’s Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching

Bukhbinder

Ling

Hasan³

et al. 2022

JAD

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“…In support of this, a lower risk for dementia following adult tetanus, diphtheria, and pertussis vaccination has been documented (6). Other vaccinations [Bacille Calmette-Guérin (BCG), influenza, COVID] may also be associated with reduced AD risk (7)(8)(9)(10).…”

Section: Abstract Background/αim: the Relationship Of Herpes Viruses And Herpes Zoster (Hz) With Dementia Andmentioning

confidence: 93%

Herpes Zoster Vaccination Reduces Risk of Dementia

Lehrer

Rheinstein²

2021

In Vivo

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“…Two independent studies in the United States showed a similar picture. Kim et al (2021) in a retrospective study of a cohort of 1290 NMIBC racially/ethnically diverse patients, 25% of whom were given BCG, found a 60% reduction of risk of AD and other dementia ( Guancial et al, 2015 ). In a study of 26,584 patients with high-risk NMIBC, Makrakis et al (2021) found that patients with any exposure to BCG (13,477) had a significant 27% lower risk for Alzheimer’s disease compared with no exposure after adjusting for age, sex, race, T-stage, and Charlson Comorbidity Index ( Klinger et al, 2021 ).…”

Section: Independent Confirmation Of the Bacillus Calmette–guérin Eff...mentioning

confidence: 99%

Bacillus Calmette–Guérin in Immuno-Regulation of Alzheimer’s Disease

Klein

Greenblatt

Gofrit

et al. 2022

Front. Aging Neurosci.

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Bacillus Calmette–Guérin is frequently the treatment of choice of superficial bladder cancer. Exposing the urinary bladder of elderly patients with bladder cancer to the BCG vaccine reduced the risk of Alzheimer’s disease (AD) substantially. Vaccines against other infectious microorganisms by other vaccination methods showed a similar but a lesser effect. This suggests that immune effects on AD are antigenically non-specific, likely being a metabolic result of immune system activation, similar to that shown for Juvenile diabetes. In this mini review we point to the benefit of BCG vaccine. We then briefly highlight the pathological involvement of the immune system in the AD both, in the peripheral and the central (brain) compartments. Given the uncertain prophylactic mechanism of the BCG effect against AD we propose to take advantage of the therapeutically planned bladder exposure to BCG. Based on pathological aggregation of wrongly cleaved amyloid precursor protein (APP) resistant to the unfolded protein response (UPR) which results in amyloid beta plaques we predict that BCG may impact the UPR signaling cascade. In addition pathways of innate immunity training concerned with energy metabolism, predict capability of activated immune cells to substitute deranged astrocytes that fail to support neuronal energy metabolism. This mini review points to ways through which immune cells can mediate between BCG vaccination and AD to support the wellness of the central nervous system.

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Intravesical Bacillus Calmette-Guérin Treatment Is Inversely Associated With the Risk of Developing Alzheimer Disease or Other Dementia Among Patients With Non–muscle-invasive Bladder Cancer

Cited by 21 publications

References 27 publications

Risk of Alzheimer’s Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching

Risk of Alzheimer’s Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching

Herpes Zoster Vaccination Reduces Risk of Dementia

Bacillus Calmette–Guérin in Immuno-Regulation of Alzheimer’s Disease

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