{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T03:46:23Z","timestamp":1792727183290,"version":"4.5.0"},"reference-count":73,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T00:00:00Z","timestamp":1620691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2753\/20"],"award-info":[{"award-number":["2753\/20"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Bacillus Calmette\u2013Guerin (BCG) is a live attenuated form of Mycobacterium bovis that was developed 100 years ago as a vaccine against tuberculosis (TB) and has been used ever since to vaccinate children globally. It has also been used as the first-line treatment in patients with nonmuscle invasive bladder cancer (NMIBC), through repeated intravesical applications. Numerous studies have shown that BCG induces off-target immune effects in various pathologies. Accumulating data argue for the critical role of the immune system in the course of neurodegenerative diseases such as Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD). In this study, we tested whether repeated exposure to BCG during the treatment of NMIBC is associated with the risk of developing AD and PD. We presented a multi-center retrospective cohort study with patient data collected between 2000 and 2019 that included 12,185 bladder cancer (BC) patients, of which 2301 BCG-treated patients met all inclusion criteria, with a follow-up of 3.5 to 7 years. We considered the diagnosis date of AD and nonvascular dementia cases for BC patients. The BC patients were partitioned into those who underwent a transurethral resection of the bladder tumor followed by BCG therapy, and a disjoint group that had not received such treatment. By applying Cox proportional hazards (PH) regression and competing for risk analyses, we found that BCG treatment was associated with a significantly reduced risk of developing AD, especially in the population aged 75 years or older. The older population (\u226575 years, 1578 BCG treated, and 5147 controls) showed a hazard ratio (HR) of 0.726 (95% CI: 0.529\u20130.996; p-value = 0.0473). While in a hospital-based cohort, BCG treatment resulted in an HR of 0.416 (95% CI: 0.203\u20130.853; p-value = 0.017), indicating a 58% lower risk of developing AD. The risk of developing PD showed the same trend with a 28% reduction in BCG-treated patients, while no BCG beneficial effect was observed for other age-related events such as Type 2 diabetes (T2D) and stroke. We attributed BCG\u2019s beneficial effect on neurodegenerative diseases to a possible activation of long-term nonspecific immune effects. We proposed a prospective study in elderly people for testing intradermic BCG inoculation as a potential protective agent against AD and PD.<\/jats:p>","DOI":"10.3390\/vaccines9050491","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T22:53:40Z","timestamp":1620773620000},"page":"491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Bladder Cancer Immunotherapy by BCG Is Associated with a Significantly Reduced Risk of Alzheimer\u2019s Disease and Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"9","author":[{"given":"Danielle","family":"Klinger","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6881-5770","authenticated-orcid":false,"given":"Brian L.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of California Los Angeles, Los Angeles, CA 90095-1596, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-235X","authenticated-orcid":false,"given":"Noam","family":"Barda","sequence":"additional","affiliation":[{"name":"Clalit Research Institute, Innovation Division, Clalit Health Services, Ramat-Gan 6578898, Israel"},{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eran","family":"Halperin","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of California Los Angeles, Los Angeles, CA 90095-1596, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8815-6488","authenticated-orcid":false,"given":"Ofer N.","family":"Gofrit","sequence":"additional","affiliation":[{"name":"Department of Urology, Hadassah University Hospital, Jerusalem 91904, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Greenblatt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91904, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7218-2558","authenticated-orcid":false,"given":"Nadav","family":"Rappoport","sequence":"additional","affiliation":[{"name":"Department of Software and Information Systems Engineering, Faculty of Engineering Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9357-4526","authenticated-orcid":false,"given":"Michal","family":"Linial","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7297-3029","authenticated-orcid":false,"given":"Herv\u00e9","family":"Bercovier","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91904, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.3389\/fimmu.2017.01134","article-title":"What have we learnt about BCG vaccination in the last 20 years?","volume":"8","author":"Dockrell","year":"2017","journal-title":"Front. 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