{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:38:05Z","timestamp":1792802285793,"version":"4.5.0"},"reference-count":15,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T00:00:00Z","timestamp":1702512000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Schmekel funder for Urological research."},{"name":"Center for Clinical Research, S\u00f6rmland, Uppsala University","id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) affects 50 million people worldwide. The immune system plays a major role in the pathogenesis of AD. Several retrospective analyses have reported a decreased risk of AD and other dementias in bladder cancer patients treated with immunotherapy in the form of Bacillus Calmette-Guerin (BCG) bladder instillations. We tested this hypothesis in a Swedish population-based prospective cohort of patients with non-muscle invasive bladder cancer (NMIBC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>We utilized the BladderBaSe 2.0 database, which contains tumor-specific, health-related, and socio-demographic information for patients diagnosed with NMIBC between 1997 and 2019. The database also includes a matched comparison cohort sampled from the general population, consisting of individuals free from urinary tract cancer at the time of the index case\u2019s diagnosis. Five controls were randomly selected for each index case without replacement on the date of the index case\u2019s diagnosis. Our inclusion criteria identified participants diagnosed with NMIBC who had received BCG as primary treatment, along with their corresponding comparison cohort. We excluded those diagnosed with dementia before or within 6 months of NMIBC diagnosis. To compare the NMIBC cohort with their matched comparison cohort, we used a stratified Cox model, treating each case with its controls as a stratum. We identified 38,934 patients in the NMIBC cohort, with 6,496 receiving BCG after primary diagnosis (cases). AD\/dementia was diagnosed during follow-up in 6.1% of cases and 7.4% of controls. Cases had a slightly lower risk of dementia than controls, with a hazard ratio (HR) of 0.88 (95% confidence interval [CI] 0.780\u20130.991), and a HR of 0.89 (CI 0.703\u20131.119) for AD. Subgroup analysis for dementia showed that age over 75 years had an HR of 0.73 (CI 0.616\u20130.863), and female gender had an HR of 0.73 (CI 0.552\u20130.971). The associations were similar for AD specifically, but not statistically significant. Similar to previous studies, we analyzed bladder cancer patients treated with and without BCG therapy. Multivariate Cox analysis indicated that those treated with BCG had a lower risk of dementia (HR 0.81, 95% CI 0.71\u20130.92), and an HR of 0.98 (95% CI 0.75\u20131.27) for AD specifically. High age was a significant risk modifier; the HR was 3.8 (CI 3.44\u20134.11) for dementia and 3.1 (CI 2.59\u20133.73) for AD. Even patients not receiving BCG had a significantly lower risk for AD than controls (HR 0.86, CI 0.77\u20130.96).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study observed a marginally decreased risk of developing AD\/dementia associated with earlier intravesical BCG treatment in NMIBC patients. This small benefit was most pronounced in those with high age and female gender. The disparity from previous highly positive studies underscores the importance of using an appropriate control cohort.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0292174","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T13:36:25Z","timestamp":1702560985000},"page":"e0292174","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia.\u2014A Swedish nationwide cohort study from 1997 to 2019"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1825-8547","authenticated-orcid":true,"given":"Eugen","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oskar","family":"Hagberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per-Uno","family":"Malmstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,12,14]]},"reference":[{"key":"pone.0292174.ref001","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.trci.2018.06.014","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease","volume":"4","author":"JW Kinney","year":"2018","journal-title":"Alzheimers Dement (N Y)"},{"key":"pone.0292174.ref002","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s40425-017-0280-z","article-title":"Society for immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinorma","volume":"5","author":"AM Kamat","year":"2017","journal-title":"J Immunother Cancer"},{"issue":"7","key":"pone.0292174.ref003","first-page":"200","article-title":"Nonspecific immune stimulation with BCG in Herpes simplex recidivans","volume":"104","author":"G. Hippmann","year":"1992","journal-title":"Follow-up 5 to 10 years after BCG vaccination. Wien Klin Wochenschr"},{"key":"pone.0292174.ref004","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1586\/1744666X.2014.909286","article-title":"The interplay between bacillus Calmette-Guerin and Treg cells and its role to prevent or cure inflammatory diseases","volume":"10","author":"M. Lagranderie","year":"2014","journal-title":"Expert. Rev. Clin. Immunol"},{"key":"pone.0292174.ref005","doi-asserted-by":"crossref","first-page":"e409","DOI":"10.1016\/j.clgc.2021.05.001","article-title":"Intravesical Bacillus Calmette-Guerin Treatment Is Inversely Associated With the Risk of Developing Alzheimer Disease or Other Dementia Among Patients With Non-muscle-invasive Bladder Cancer.","volume":"19","author":"J. I. Kim","year":"2021","journal-title":"Clin. Genitourin. Cancer"},{"issue":"4","key":"pone.0292174.ref006","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1097\/WAD.0000000000000530","article-title":"Intravesical BCG and Incidence of Alzheimer Disease in Patients With Bladder Cancer: Results From an Administrative Dataset.","volume":"36","author":"D Makrakis","year":"2022","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"11","key":"pone.0292174.ref007","doi-asserted-by":"crossref","first-page":"e0224433","DOI":"10.1371\/journal.pone.0224433","article-title":"Bacillus Calmette-Gu\u00e9rin (BCG) therapy lowers the incidence of Alzheimer\u2019s disease in bladder cancer patients.","volume":"14","author":"ON Gofrit","year":"2019","journal-title":"PLoS One"},{"key":"pone.0292174.ref008","unstructured":"Nationellt kvalitetsregister f\u00f6r urinbl\u00e5secancer. Regional cancer centres in collaboration. Available: https:\/\/statistik.incanet.se\/Urinblasecancer"},{"issue":"12","key":"pone.0292174.ref009","doi-asserted-by":"crossref","first-page":"e064898","DOI":"10.1136\/bmjopen-2022-064898","article-title":"Cohort profile: Bladder Cancer Data Base Sweden (BladderBaSe) 2.0.","volume":"12","author":"C H\u00e4ggstr\u00f6m","year":"2022","journal-title":"BMJ Open."},{"key":"pone.0292174.ref010","volume-title":"R: A language and environment for statistical computing.","author":"R Core Team","year":"2022"},{"key":"pone.0292174.ref011","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3390\/vaccines9050491","article-title":"Bladder Cancer Immunotherapy by BCG Is Associated with a Significantly Reduced Risk of Alzheimer\u2019s Disease and Parkinson\u2019s Disease.","volume":"9","author":"D. Klinger","year":"2021","journal-title":"Vaccines"},{"issue":"4","key":"pone.0292174.ref012","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3109\/21681805.2014.1000963","article-title":"Local recurrence and progression of non-muscle-invasive bladder cancer in Sweden: a population-based follow-up study","volume":"49","author":"F Liedberg","year":"2015","journal-title":"Scand J Urol"},{"issue":"4","key":"pone.0292174.ref013","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.3233\/JAD-170572","article-title":"Detection of Dementia Cases in Two Swedish Health Registers: A Validation Study","volume":"61","author":"D Rizzuto","year":"2018","journal-title":"J Alzheimers Dis"},{"issue":"1","key":"pone.0292174.ref014","doi-asserted-by":"crossref","first-page":"367","DOI":"10.3233\/JAD-220436","article-title":"Risk of Dementia in Cancer Survivors: A Meta-Analysis of Population-Based Cohort Studies","volume":"89","author":"DD Zhang","year":"2022","journal-title":"J Alzheimers Dis"},{"key":"pone.0292174.ref015","doi-asserted-by":"crossref","first-page":"110723","DOI":"10.1016\/j.pnpbp.2023.110723","article-title":"Nicotine\u2019s effect on cognition, a friend or foe","volume":"124","author":"Q Wang","year":"2023","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0292174","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T13:36:44Z","timestamp":1702561004000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0292174"}},"subtitle":[],"editor":[{"given":"Robert Jeenchen","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,12,14]]},"references-count":15,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0292174","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,14]]}}}