{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:56:28Z","timestamp":1792652188794,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,12]],"date-time":"2022-02-12T00:00:00Z","timestamp":1644624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>BCG vaccine has been used for 100 years to prevent tuberculosis. Not all countries, including the United States, adopted the initial World Health Organization recommendation to use BCG. Moreover, many Western countries that had routinely used BCG have discontinued its use. Recent population studies demonstrate lower prevalence of Alzheimer\u2019s disease (AD) in countries with high BCG coverage. Intravesicular instillation of BCG is also used to treat bladder cancer that has not invaded the bladder muscle wall and has been shown to reduce recurrence. Several retrospective studies of bladder cancer patients demonstrated that BCG treatment was associated with a significantly reduced risk of developing AD. Plasma amyloid \u03b2 assessment has become a fertile area of study for an AD biomarker that is predictive of a positive amyloid PET scan. Mass spectrometry-based plasma amyloid 42\/40 ratio has proven to be accurate and robust, and when combined with age and ApoE, is shown to accurately predict current and future brain amyloid status. These parameters, amyloid 42\/40 ratio, age and ApoE genotype are incorporated into an Amyloid Probability Score (APS)\u2013a score that identifies low, intermediate or high risk of having a PET scan positive for cerebral amyloid. Community recruitment was used for this open-label pilot study. Forty-nine BCG-na\u00efve, immunocompetent individuals completed our study: prior to BCG prime and boost, as determined by the APS, 34 had low risk (APS 0\u201335), 5 had intermediate risk (APS 36\u201357) and 10 had high risk (APS 58\u2013100). The APS range for the participant group was 0 to 94. Follow-up plasma amyloid testing 9 months after vaccination revealed a reduction in the APS in all the risk groups: low risk group (p = 0. 37), intermediate risk group (p = 0.13) and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk. The small number of participants and the nascent status of plasma amyloid testing will rightfully temper embracement of these results. However, both the favorable direction of change after BCG as well as the utility of the APS\u2014a valuable surrogate AD biomarker\u2014may prompt a definitive large-scale multicenter investigation of BCG and AD risk as determined by plasma amyloid peptide ratios and APS.<\/jats:p>","DOI":"10.3390\/microorganisms10020424","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T20:34:45Z","timestamp":1644784485000},"page":"424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"10","author":[{"given":"Coad Thomas","family":"Dow","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53706, USA"},{"name":"Mindful Diagnostics and Therapeutics, Eau Claire, WI 54701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Greenblatt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Hebrew University, Jerusalem 9103401, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7612-7727","authenticated-orcid":false,"given":"Edward D.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Academic Affairs, National Jewish Health, Denver, CO 80218, USA"},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80217, USA"},{"name":"Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan F.","family":"Dow","sequence":"additional","affiliation":[{"name":"Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"},{"name":"Northwestern Wisconsin Region Mayo Clinic Health System, Eau Claire, WI 54703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,12]]},"reference":[{"key":"ref_1","first-page":"1481","article-title":"Preventive Vaccination Against Tuberculosis with BCG","volume":"24","author":"Calmette","year":"1931","journal-title":"Proc. R. Soc. Med."},{"key":"ref_2","unstructured":"(2022, February 10). Available online: https:\/\/www.ciil.fr\/bcg-symposium\/scientific-program."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gofrit, O.N., Klein, B.Y., Cohen, I.R., Ben-Hur, T., Greenblatt, C.L., and Bercovier, H. (2019). Bacillus Calmette-Gu\u00e9rin (BCG) therapy lowers the incidence of Alzheimer\u2019s disease in bladder cancer patients. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0224433"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.mehy.2019.01.007","article-title":"Can immunization with Bacillus Calmette-Gu\u00e9rin (BCG) protect against Alzheimer\u2019s disease?","volume":"123","author":"Gofrit","year":"2019","journal-title":"Med. Hypotheses"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.nbd.2017.02.001","article-title":"Immunization with Bacillus Calmette-Gu\u00e9rin (BCG) alleviates neuroinflammation and cognitive deficits in APP\/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain","volume":"101","author":"Zuo","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1001\/jama.2015.4668","article-title":"Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis","volume":"313","author":"Jansen","year":"2015","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1001\/jamaneurol.2019.1971","article-title":"Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging\u2013Alzheimer\u2019s Association Research Framework","volume":"76","author":"Jack","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1647","DOI":"10.1212\/WNL.0000000000008081","article-title":"High-precision plasma \u03b2-amyloid 42\/40 predicts current and future brain amyloidosis","volume":"93","author":"Schindler","year":"2019","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13195-019-0485-0","article-title":"Advantages and disadvantages of the use of the CSF Amyloid \u03b2 (A\u03b2) 42\/40 ratio in the diagnosis of Alzheimer\u2019s Disease","volume":"11","author":"Hansson","year":"2019","journal-title":"Alzheimers Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cca.2021.05.011","article-title":"The PrecivityAD\u2122 test: Accurate and reliable LC-MS\/MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E proteotype for the assessment of brain amyloidosis","volume":"519","author":"Kirmess","year":"2021","journal-title":"Clin. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1099\/vir.0.036004-0","article-title":"Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans","volume":"92","author":"Derhovanessian","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.virusres.2010.09.010","article-title":"Role of CMV in immune senescence","volume":"157","author":"Pawelec","year":"2011","journal-title":"Virus Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1093\/infdis\/jit210","article-title":"Virological and Immunological Characteristics of Human Cytomegalovirus Infection Associated With Alzheimer Disease","volume":"208","author":"Lurain","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Westman, G., Berglund, D., Wid\u00e9n, J., Ingelsson, M., Korsgren, O., Lannfelt, L., Sehlin, D., Lidehall, A.-K., and Eriksson, B.-M. (2014). Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer\u2019s Disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096779"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"939","DOI":"10.3233\/JAD-161305","article-title":"Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer\u2019s Disease Development","volume":"61","author":"Olsson","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3233\/JAD-2009-1015","article-title":"Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer\u2019s disease","volume":"17","author":"Larbi","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s00262-005-0109-3","article-title":"Immunosenescence, suppression and tumour progression","volume":"55","author":"Pawelec","year":"2006","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1023\/A:1024580531705","article-title":"Large Numbers of Dysfunctional CD8+ T Lymphocytes Bearing Receptors for a Single Dominant CMV Epitope in the Very Old","volume":"23","author":"Ouyang","year":"2003","journal-title":"J. Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1016\/j.jalz.2016.06.001","article-title":"Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population-based elderly cohort","volume":"12","author":"Dage","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13195-021-00944-y","article-title":"Comparison of plasma neurofilament light and total tau as neurodegeneration markers: Associations with cognitive and neuroimaging outcomes","volume":"13","author":"Marks","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nri.2016.43","article-title":"Harnessing the beneficial heterologous effects of vaccination","volume":"16","author":"Goodridge","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Faustman, D.L., Wang, L., Okubo, Y., Burger, U., Ban, L., Man, G., Zheng, H., Schoenfeld, D., Pompei, R., and Avruch, J. (2012). Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041756"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.coi.2018.09.016","article-title":"Bridging the gap between vaccination with Bacille Calmette-Gu\u00e9rin (BCG) and immunological tolerance: The cases of type 1 diabetes and multiple sclerosis","volume":"55","author":"Ristori","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1054\/tube.2000.0271","article-title":"Optimal models to evaluate the protective efficacy of tuberculosis vaccines","volume":"81","author":"Griffin","year":"2001","journal-title":"Tuberculosis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"234","DOI":"10.3389\/fimmu.2019.00234","article-title":"BCG Vaccination Induces, M. avium and M. abscessus Cross-Protective Immunity","volume":"10","author":"Abate","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1093\/cid\/ciy241","article-title":"Increase in Childhood Nontuberculous Mycobacterial Infections After Bacille Calmette-Gu\u00e9rin Coverage Drop: A Nationwide, Population-Based Retrospective Study, Finland, 1995\u20132016","volume":"67","author":"Kontturi","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/0962-8479(94)90080-9","article-title":"Six years\u2019 experience with the discontinuation of BCG vaccination: 4. Protective effect of BCG vaccination against the Mycobacterium avium intracellulare complex","volume":"75","author":"Trnka","year":"1994","journal-title":"Tuber. Lung Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1473-3099(06)70412-1","article-title":"The role of BCG in prevention of leprosy: A meta-analysis","volume":"6","author":"Setia","year":"2006","journal-title":"Lancet Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0035-9203(76)90128-0","article-title":"The protective effect of BCG against Mycobacterium ulcerans disease: A controlled trial in an endemic area of Uganda","volume":"70","author":"Smith","year":"1976","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1093\/infdis\/jiy207","article-title":"Does BCG Vaccination Protect Against Nontuberculous Mycobacterial Infection? A Systematic Review and Meta-Analysis","volume":"218","author":"Zimmermann","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"714179","DOI":"10.3389\/fimmu.2021.714179","article-title":"Warm, Sweetened Milk at the Twilight of Immunity-Alzheimer\u2019s Disease-Inflammaging, Insulin Resistance, M. paratuberculosis and Immunosenescence","volume":"12","author":"Dow","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dow, C.T. (2020). Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases. Microorganisms, 8.","DOI":"10.3390\/microorganisms8020212"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.cmi.2019.04.020","article-title":"Non-specific effects of BCG vaccine on viral infections","volume":"25","author":"Moorlag","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ramos-Martinez, E., Falf\u00e1n-Valencia, R., P\u00e9rez-Rubio, G., Andrade, W.A., Rojas-Serrano, J., Ambrocio-Ortiz, E., Galicia-\u00c1lvarez, D.S., B\u00e1rcenas-Montiel, I., Velasco-Medina, A., and Vel\u00e1zquez-S\u00e1mano, G. (2021). Effect of BCG Revaccination on Occupationally Exposed Medical Personnel Vaccinated against SARS-CoV-2. Cells, 10.","DOI":"10.3390\/cells10113179"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41541-021-00406-4","article-title":"A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection","volume":"6","author":"Counoupas","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e20211862","DOI":"10.1084\/jem.20211862","article-title":"Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge","volume":"219","author":"Hilligan","year":"2022","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s00401-010-0789-4","article-title":"The pathological process underlying Alzheimer\u2019s disease in individuals under thirty","volume":"121","author":"Braak","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"S41","DOI":"10.1016\/j.metabol.2017.01.014","article-title":"Alzheimer\u2019s disease: Innate immunity gone awry?","volume":"69","author":"VanItallie","year":"2017","journal-title":"Metabolism"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"69347","DOI":"10.18632\/oncotarget.12469","article-title":"Neuroprotective effects of CD4+CD25+Foxp3+ regulatory T cells in a 3xTg-AD Alzheimer\u2019s disease model","volume":"7","author":"Baek","year":"2016","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1212\/01.wnl.0000438216.93319.ab","article-title":"Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS","volume":"82","author":"Ristori","year":"2014","journal-title":"Neurology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6201","DOI":"10.4049\/jimmunol.181.9.6201","article-title":"Mycobacterium bovisBacille Calmette-Gu\u00e9rin Infection in the CNS Suppresses Experimental Autoimmune Encephalomyelitis and Th17 Responses in an IFN-\u03b3-Independent Manner","volume":"181","author":"Lee","year":"2008","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1093\/gerona\/glab115","article-title":"Lower Risk for Dementia Following Adult Tetanus, Diphtheria, and Pertussis (Tdap) Vaccination","volume":"76","author":"Scherrer","year":"2021","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Scherrer, J.F., Salas, J., Wiemken, T.L., Hoft, D.F., Jacobs, C., and Morley, J.E. (2021). Impact of herpes zoster vaccination on incident dementia: A retrospective study in two patient cohorts. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0257405"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wiemken, T.L., Salas, J., Morley, J.E., Hoft, D.F., Jacobs, C., and Scherrer, J.F. (2021). Comparison of rates of dementia among older adult recipients of two, one, or no vaccinations. J. Am. Geriatr. Soc.","DOI":"10.1111\/jgs.17606"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"692729","DOI":"10.3389\/fimmu.2021.692729","article-title":"BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity","volume":"12","author":"Eggenhuizen","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/cti2.1227","article-title":"Identification of similar epitopes between severe acute respiratory syndrome coronavirus-2 and Bacillus Calmette\u2013Gu\u00e9rin: Potential for cross-reactive adaptive immunity","volume":"9","author":"Paragi","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Koster, K.J., Webb, H.L., and Cirillo, J.D. (2021). COVID-19 and Beyond: Exploring Public Health Benefits from Non-Specific Effects of BCG Vaccination. Microorganisms, 9.","DOI":"10.3390\/microorganisms9102120"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/10\/2\/424\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:18:08Z","timestamp":1760134688000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/10\/2\/424"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,12]]},"references-count":47,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["microorganisms10020424"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms10020424","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,12]]}}}