New research led by Mass General Brigham investigators suggests that the Bacillus Calmette-Guérin (BCG) vaccine — which is delivered through the skin to prevent tuberculosis — may remodel the human brain's immune environment, offering a potential biological explanation for previously observed associations between BCG vaccination and lower Alzheimer's disease risk. The year-long study found that BCG promoted increased responsiveness in immune cells surrounding the brain and modified Alzheimer's-related biomarkers in older adults without evidence of Alzheimer's pathology, but not in those with biomarker evidence of the disease. Findings are published in Communications Medicine .
"The immune system and the brain may be far more connected than we once thought," said senior and co-corresponding author Steven Arnold, MD, managing director of the Interdisciplinary Brain Center at Mass General Brigham Neuroscience Institute. "The next step is to test this rigorously in larger, controlled studies, particularly in prevention, where the hope would be to preserve brain health before significant Alzheimer's disease develops."
Over the last two decades, researchers at Mass General Brigham have been studying multiple "off-target" benefits of the BCG vaccine in autoimmunity and infection, including ongoing Phase III clinical trials in type 1 diabetes and past Phase II and Phase III trials in COVID-19 . Prior research involving preclinical models, retrospective studies, and randomized clinical trials has suggested that BCG can also reduce Alzheimer's risk and bring about trained immunity, boosting defenses against unrelated infections and correcting blood sugars. Most prior research on trained immunity has focused on blood, leaving unclear whether BCG influences immune cells in the fluid surrounding the brain and spinal cord as well.
Seeking insight, the research team conducted two related one-year, open-label clinical trials of BCG immunotherapy in 23 adults aged 55 years and older. The cohort included 11 adults with Alzheimer's pathology and 12 adults without. Cerebrospinal fluid (CSF) and peripheral blood samples were obtained from participants at regular intervals after vaccination.
The study, which was led by co-first authors Marc Weinberg, MD, PhD, Mahesh Chandra Kodali, PhD, and Zhaozhi Li, PhD, found that BCG promoted enhanced immune responses to other immune challenges, suggesting broader effects on immune function. Notably, the heightened immune responsiveness was not accompanied by an increase in inflammatory markers, which is a known risk factor for neurodegeneration.
BCG also shifted the levels of amyloid-beta (a key biomarker of Alzheimer's disease) in the CSF and bloodstream. In healthier participants without Alzheimer's disease pathology, amyloid levels declined significantly in brain and spinal fluid, while increasing in blood samples over 12 months. This shift in balance was not observed in participants with Alzheimer's pathology, indicating no measurable effect in this group, and suggesting that the timing of administering BCG might affect early disease dynamics and protein clearance from the central nervous system.
The authors note that further research, including placebo-controlled studies, are needed to investigate the relationship between BCG and Alzheimer's disease. They also noted that the study tested a specific vaccination strategy in older adults and does not examine the effect of BCG vaccination in childhood, which is common in many countries in sub-Saharan Africa, Southeast Asia, and parts of Eastern Europe due to the prevalence of tuberculosis in these regions.
"Vaccines have traditionally been viewed through the lens of infectious disease prevention," said Weinberg, who contributed to the study while working as a research scientist at Mass General Brigham. Weinberg is now an employee at AbbVie. "Although more research is needed, these findings suggest they may also influence biological processes involved in brain aging and neurodegenerative disease."
Authorship: In addition to Weinberg and Arnold, Mass General Brigham authors include Mahesh Chandra Kodali, Jake A. Galler, Arianna R. Tidball, William Cody Reynolds, Cathrine Young, Kelli Devitte-McKee, Hadia A. Fatima, Pia Kivisäkk, Willem M. Kühtreiber, Jessica Gerber, Alison J. McManus, Rudolph E. Tanzi, Sudeshna Das, and Denise L. Faustman. Additional authors include Zhaozhi Li, Mandovi Chatterjee, Arpita Kulkarni, James M. Billingsly, Alexandra L. Bartlett, and Shannan Ho Sui.
Disclosures: Weinberg is an employee of AbbVie Inc. The research reported here was conducted at Massachusetts General Hospital and Harvard Medical School, and AbbVie Inc. had no role in the design, conduct, or reporting of the study. Galler, Arnold, Kodali, Tidball, Reynolds, Gerber, Young, McManus, Devitte-McKee, Kivisäkk, Tanzi, Das, Faustman, and Kühtreiber are employees of The General Hospital Corporation (Massachusetts General Hospital). Faustman reports no consulting fees, funding, or involvement in trial design or manuscript preparation from the drug owner. All other authors declare no competing interests.
Funding: This project was funded by the National Institutes of Health (R25MH094612, T32-MH112485, U13AG067696, UL1 TR002541), National Institute on Aging (P30AG062421, UM1TR004408), the Alzheimer's Association (AACSF-22-970716, PTC REG-20-653582), the Massachusetts Life Sciences Center, and the Cure Alzheimer's Fund.
Paper cited: Weinberg MS et al. "Bacillus Calmette–Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer's biomarkers: results from two open-label clinical trials" Communications Medicine DOI: 10.1038/s43856-026-01691-7
