Bacillus Calmette-Guérin (BCG) therapy lowers the incidence of Alzheimer’s disease in bladder cancer patients

Autoři: Ofer N. Gofrit aff001;  Benjamin Y. Klein aff002;  Irun R. Cohen aff003;  Tamir Ben-Hur aff004;  Charles L. Greenblatt aff002;  Hervé Bercovier aff002
Působiště autorů: Department of Urology, Hadassah- Hebrew University Medical Center, Jerusalem, Israel aff001;  Department of Microbiology and Molecular Genetics, Hebrew University Jerusalem, Israel aff002;  Department of Immunology, Weizmann Institute, Rehovot, Israel aff003;  Department of Neurology Hadassah-Hebrew University Medical Center, Jerusalem, Israel aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224433



Alzheimer’s disease (AD) affects one in ten people older than 65 years. Thus far, there is no cure or even disease-modifying treatment for this disease. The immune system is a major player in the pathogenesis of AD. Bacillus Calmette-Guérin (BCG), developed as a vaccine against tuberculosis, modulates the immune system and reduces recurrence of non-muscle invasive bladder cancer. Theoretical considerations suggested that treatment with BCG may decrease the risk of AD. We tested this hypothesis on a natural population of bladder cancer patients.

Methods and findings

After removing all bladder cancer patients presenting with AD or developing AD within one-year following diagnosis of bladder cancer, we collected data on a total of 1371 patients (1134 males and 237 females) who were followed for at least one year after the diagnosis of bladder cancer. The mean age at diagnosis of bladder cancer was 68.1 years (SD 13.0). Adjuvant post-operative intra-vesical treatment with BCG was given to 878 (64%) of these patients. The median period post-operative follow-up was 8 years. During follow-up, 65 patients developed AD at a mean age of 84 years (SD 5.9), including 21 patients (2.4%) who had been treated with BCG and 44 patients (8.9%) who had not received BCG. Patients who had been treated with BCG manifested more than 4-fold less risk for AD than those not treated with BCG. The Cox proportional hazards regression model and the Kaplan-Meier analysis of AD free survival both indicated high significance: patients not treated with BCG had a significantly higher risk of developing AD compared to BCG treated patients (HR 4.778, 95%CI: 2.837–8.046, p = 4.08x10-9 and Log Rank Chi-square 42.438, df = 1, p = 7.30x10-11, respectively). Exposure to BCG did not modify the prevalence of Parkinson’s disease, 1.9% in BCG treated patients and 1.6% in untreated (Fisher’s Exact Test, p = 1).


Bladder cancer patients treated with BCG were significantly less likely to develop AD at any age than patients who were not so treated. This finding of a retrospective study suggests that BCG treatment might also reduce the incidence of AD in the general population. Confirmation of such effects of BCG in other retrospective studies would support prospective studies of BCG in AD.

Klíčová slova:

Alzheimer's disease – Bladder cancer – Cancer detection and diagnosis – Cancer treatment – Cytokines – Immune system – Mouse models – Vaccination and immunization


1. Prince M, Comas-Herrera A, Knapp M, Guerchet M. World Alzheimer Report 2016: Improving Healthcare for People Living with Dementia: Coverage, Quality and Costs Now and in the Future. London: Alzheimer’s Disease International; 2016.


3. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM et al. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y). 2018; 4: 575–590. doi: 10.1016/j.trci.2018.06.014 30406177

4. Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, et al. Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease. Engl J Med. 2019; 380: 1408–1420. doi: 10.1056/NEJMoa1812840 30970186

5. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018; 378: 321–330. doi: 10.1056/NEJMoa1705971 29365294

6. Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016; 388: 2873–2884. doi: 10.1016/S0140-6736(16)31275-2 27863809

7. Jobke B, McBride T, Nevin L, Peiperl L, Ross A, Stone C, et al. as the PLOS Medicine Editors. Setbacks in Alzheimer research demand new strategies, not surrender. PLoS Med. 2018;15(2):e1002518. doi: 10.1371/journal.pmed.1002518 29486005

8. Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011; 121:171–181. doi: 10.1007/s00401-010-0789-4 21170538

9. VanItallie TB Alzheimer's disease: Innate immunity gone awry? Metabolism. 2017; 69S:S41–S49. doi: 10.1016/j.metabol.2017.01.014 28129888

10. Baek H, Ye M, Kang GH, Lee C et al. Neuroprotective effects of CD4+CD25+Foxp3+ regulatory T cells in a 3xTg-AD Alzheimer's disease model. Oncotarget. 2016; 7: 69347–69357. doi: 10.18632/oncotarget.12469 27713140

11. Li Y, Liu X, Wang W, Wang S Zhang J, Jiang S et al. Low-dose IL-2 expands CD4+ regulatory T cells with a suppressive function in vitro via the STAT5-dependent pathway in patients with chronic kidney diseases. Ren Fail. 2018; 40: 280–288. doi: 10.1080/0886022X.2018.1456462 29619880

12. Kamat AM, Bellmunt J, Galsky MD, Konety BR et al. Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. J Immunother Cancer. 2017; 5: 80. doi: 10.1186/s40425-017-0280-z 28962591

13. Gofrit ON, Bercovier H, Klein BY, Cohen IR, Ben-Hur T, Greenblatt CL. Can immunization with Bacillus Calmette-Guérin (BCG) protect against Alzheimer's disease? Med Hypotheses. 2019; 123:95–97. doi: 10.1016/j.mehy.2019.01.007 30696606

14. Ristori G, Romano S, Cannoni S, Visconti A, Mendozzi L, Cecconi P, et al. Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology 2014; 82: 41–8. doi: 10.1212/01.wnl.0000438216.93319.ab 24306002

15. Lee JE, Reinke EK, Zozulya AL, Sandor M et al. Mycobacterium bovis Bacille Calmette-Guerin Infection in the CNS Suppresses Experimental Autoimmune Encephalomyelitis and Th17 Responses in an IFN-ᵧ -Independent Manner. J Immunol 2008; 181: 6201–6212. doi: 10.4049/jimmunol.181.9.6201 18941210.

16. Zuo Z, Qi F, Yang J, Wang X et al. Immunization with Bacillus Calmette-Guérin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain. Neurobiol Dis. 2017; 101: 27–39. doi: 10.1016/j.nbd.2017.02.001 28189498

17. Gofrit ON, Pode D, Pizov G, Duvdevani M, Landau EH, Hidas G, Yutkin V. 'Very-low-risk' bladder tumours—a new entity? BJU Int. 2018;121: 627–631. doi: 10.1111/bju.14108 29274202

18. Aarts S, van den Akker M, Winkens B. The importance of effect sizes. The European Journal of General Practice 2014, 20:1, 61–64. doi: 10.3109/13814788.2013.818655 23992128

19. Niu H, Álvarez-Álvarez I, Guillén-Grima F, Aguinaga-Ontoso I. Prevalence and incidence of Alzheimer's disease in Europe: A meta-analysis. Neurología. 2017;32:523–532. doi: 10.1016/j.nrl.2016.02.016 27130306

20. Nebel RA, Aggarwal NT, Barnes LL, Gallagher A, Goldstein JM, Kantarci K, Mallampalli MP, Mormino EC, Scott L, Yu WH, Maki PM, Mielke MM. Understanding the impact of sex and gender in Alzheimer's disease: A call to action. Alzheimers Dement. 2018; 14:1171–1183. doi: 10.1016/j.jalz.2018.04.008 29907423

21. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011; 204: 245–52. doi: 10.1093/infdis/jir240 21673035

22. Moorlag SJCFM Arts RJW, van Crevel R Netea MG. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019 May 2. doi: 10.1016/j.cmi.2019.04.020 PMCID: PMC31055165 31055165

23. Taniguchi K, Koga S, Nishikido M, Yamashita S Sakuragi T, Kanetake H,et al. Systemic immune response after intravesical instillation of bacille Calmette-Guérin (BCG) for superficial bladder cancer. Clin Exp Immunol. 1999; 115: 131–5. doi: 10.1046/j.1365-2249.1999.00756.x 9933432

24. Spencer BA, McBride RB, Hershman DL, Buono D, Herr HW, Benson MC, et al. Adjuvant intravesical bacillus calmette-guérin therapy and survival among elderly patients with non-muscle-invasive bladder cancer. J Oncol Pract. 2013; 9: 92–8. doi: 10.1200/JOP.2011.000480 PMCID: PMC23814517 23814517

25. Ott BR, Jones RN, Daiello LA, de la Monte SM, Stopa EG, Johanson CE, et al. Blood-Cerebrospinal Fluid Barrier Gradients in Mild Cognitive Impairment and Alzheimer's Disease: Relationship to Inflammatory Cytokines and Chemokines. Front Aging Neurosci. 2018; 10: 245. doi: 10.3389/fnagi.2018.00245 eCollection 2018. 30186149

26. Laćan G., Dang H, Middleton B, Horwitz MA, Tian J, Melega WP, Kaufman DL. Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease J Neurosci Res. 2013; 91:1292–1302. doi: 10.1002/jnr.23253 23907992

27. Qi F, Zuo Z, Yang J, Hu S, Yang Y, Yuan Q, Zou J, Guo K. Combined effect of BCG vaccination and enriched environment promote neurogenesis and spatial cognition via a shift in meningeal macrophage M2 polarization. J Neuroinflammation. 2017;14:32–. doi: 10.1186/s12974-017-0808-7 28183352

28. Bajic P, Wolfe AJ, Gupta GN. The Urinary Microbiome: Implications in Bladder Cancer Pathogenesis and Therapeutics. Urology. 2019; 126:10–15. doi: 10.1016/j.urology.2018.12.034 30615894

29. Bauer C, Collado MC, Diaz Cuevas A, Vina J, Perez Martınez G. Shifts in gut microbiota composition in an APP/PSS1 transgenic mouse model of Alzheimer’s disease during lifespan. Letters in Applied Microbiology 2018; 66: 464–471. doi: 10.1111/lam.12882 29575030

30. Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci. Rep. 2017; 7: 41802. doi: 10.1038/srep41802 28176819

31. Chamie K, Saigal CS, Lai J, Hanley JM, Setodji CM, Konety BR, et al. Compliance with guidelines for patients with bladder cancer: variation in the delivery of care. Cancer. 2011; 117: 5392–401. doi: 10.1002/cncr.26198 21780079

32. Zhu X, Zhou X, Zhang Y, Sun X, Liu H, Zhang Y. Reporting and methodological quality of survival analysis in articles published in Chinese oncology journals. Medicine (Baltimore). 2017;96(50):e9204. doi: 10.1097/MD.0000000000009204 29390340

33. Musicco M, Adorni F, Di Santo S, Prinelli F, Pettenati C, Caltagirone C, Palmer K, Russo A. Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology. 2013 23; 81: 322–8. doi: 10.1212/WNL.0b013e31829c5ec1 23843468

34. Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T et al. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ. 2012; 344: e1442. doi: 10.1136/bmj.e1442 22411920

35. Bowles EJA, Walker RL, Anderson ML, Dublin S, Crane PK, Larson EB. Risk of Alzheimer's disease or dementia following a cancer diagnosis. PLoS ONE. 2017; 12: e0179857. doi: 10.1371/journal.pone.0179857 28632787

36. Demetrius L A, Simon DK. The inverse association of cancer and Alzheimer's: a bioenergetic mechanism. 2013 J. R. Soc. Interface, 10: 20130006. doi: 10.1098/rsif.2013.0006 23427097

37. Monteiro-Maia R, Pinho RT. Oral bacillus Calmette Guerin vaccine against tuberculosis: why not? Mem Inst Oswaldo Cruz. 2014; 109: 838–45. doi: 10.1590/0074-0276140091 25317714

Článek vyšel v časopise


2019 Číslo 11