Study Advances Mechanistic Insight into Tuberculosis Vaccine’s Link to Reduced Dementia Risk
10/21/2026
Based on early research, Johns Hopkins Medicine investigators are moving the field closer to understanding the role that the vaccine may have in reducing risks for dementia while expanding knowledge about trained immunity’s potential role
Bacillus Calmette-Guerin (BCG), a vaccine widely used to prevent tuberculosis and treat bladder cancer may also have properties that reduce the risk for dementia, according to new findings in a study of mice. BCG is a live, weakened vaccine made from an altered strain of the bacterium Mycobacterium bovis. The findings from this study, which was led by a team of Johns Hopkins Medicine researchers and funded by the National Institutes of Health, published today in Science Advances.
The researchers found that mice genetically engineered to have biological symptoms of dementia and that received the BCG vaccine were less likely to show hallmark signs of the disease, such as neurofibrillary (tau) tangles in the brain, sustained immune cell activation and memory loss compared to mice that received no vaccine.
“We’re hard at work trying to understand the detailed mechanism for how it works, but this research points to early clues that aspects of trained immunity are likely driving this response,” says William Bishai, M.D., Ph.D., co-director of the Johns Hopkins Center for Tuberculosis Research.
Bishai explains that trained immunity refers to the ability of mammals’ innate immune system cells — the usual “first responders” to threats like bacteria and viruses — to take on an expanded role. Following an initial stimulus, innate immune cells, often monocytes and macrophages, learn how to identify and respond to future threats that are different from the first. (Typically, other immune system cells, like T cells, take on this type of adaptive and learned response.)
In this case, Bishai believes that myeloid cells — innate immune cells — in the central nervous system and brain are using information from BCG to recognize and help the body respond to the formation of plaques and tangles characteristic of Alzheimer’s disease and related dementias.
For this new study, Bishai and the researchers created a controlled experiment with mice with symptoms of dementia, specifically marked by tau pathology or a clumping of tau proteins in the brain representing late stages of the disease.
They divided mice into those that received the BCG vaccine and those that received a saline injection. An additional comparison group included age-matched mice that did not have dementia and that also received the saline injection.
The researchers found that mice who received BCG were about five times more likely to have signs of reduced tau deposits in their brain. They were also four times less likely to have markers of sustained inflammation — signaling that their immune cells had already likely responded to tau by clearing out some of the tangles and had created a stable or protective immune response.
Untreated mice also showed activation of 716 genes connected to Alzheimer’s disease, cell death and neuroinflammation, and BCG normalized all but nine of these. Compared to untreated mice, the mice who received BCG were less likely to have signs of brain atrophy and also more likely to live longer and perform better on tasks related to remembering and identifying objects.
“BCG seems to be reducing the degree of hyperinflammation in the brain — which is a good thing — and it may be doing it through a trained immune cell mechanism,” says Bishai. “There are a number of other characteristics of trained immunity that we are studying in the lab now.”
This research, Bishai says, is believed to be the first to study BCG and dementia in mouse models with tau pathology (specifically showing how immune cells may play a role in clearing neurofibrillary tangles). Others have found similar findings with BCG and improved cognition in amyloid mouse models — which represent earlier stages of the disease marked by plaque formation.
These findings also follow observational studies in humans — those not designed to show cause and effect — that have linked off-target effects of vaccines to a reduced incidence of dementia.
Several previous studies, which are cited in the paper, have found that BCG used as an immunotherapy for non-muscle invasive bladder cancer was linked to a 12% to 78% reduced risk of dementia throughout a three- to 15-year period. The shingles vaccine has also been linked to a 20% reduced incidence of dementia.
“This is a great example of translational science working in reverse — starting with an intriguing observation in people and then going back to the laboratory to understand why it might be happening,” says Barbara Slusher, Ph.D., M.A.S., a study author, professor of neurology at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Drug Discovery program.
Slusher cautions that researchers still need to understand more of the underlying biology before they can say who might benefit, when treatment would need to be given and whether the effect can be safely reproduced in people at risk for dementia. “If we can identify the specific immune changes that are protective, we may be able to develop even more targeted approaches for the prevention of Alzheimer’s disease.”
Additional coauthors include Somnath Shee, Meixiang Huang, Meghraj Sing Baghel, Yuxin Zheng, Shichun Lun, Santosh Yadav, Nirbhay Yadav, Carlos Ruiz-Gonzalez, Sandeep Tyagi, Eric Nuermberger, Sanjay Jain, Zaver Bhujwalla and Philip Wong.
The research was supported by NIH grants R01AI155346, P30CA006973, R01CA281075 and R01AI190038. The authors have no competing or conflicting interests.