BCG Vaccination Reduced Tau Pathology and Memory Loss in Dementia Model Mice

BCG vaccination reduced several signs of dementia in genetically engineered mice, including tau deposits, brain inflammation and memory loss. The findings give researchers a way to investigate whether the vaccine’s effects on innate immunity could help explain earlier human observations linking BCG use with lower dementia incidence. They do not establish that BCG prevents dementia in people.

The preclinical study, led by researchers at Johns Hopkins University School of Medicine and published in Science Advances, examined mice that develop tau pathology. The team reported that vaccinated animals had less brain atrophy and neuronal loss, performed better on a recognition-memory task, maintained body weight more effectively and lived longer than untreated mice. Those results make the immune response a promising research lead, while leaving the questions of human benefit, timing and safety unresolved.

Testing BCG against tau pathology

BCG, short for Bacillus Calmette-Guérin, is a live, weakened vaccine derived from an altered strain of the bacterium Mycobacterium bovis. It is used to prevent tuberculosis and as an immunotherapy for bladder cancer. The Johns Hopkins team asked whether it might also affect dementia-related disease processes, focusing on tau rather than only on amyloid plaques.

The researchers used PS19 mice, also described as P301S mice. This model overexpresses a form of tau associated with disease-related changes, including neuronal loss, neuroinflammation, neurofibrillary tangles and impaired cognition. The study authors describe tau clumping as a feature of later-stage disease. The model let them examine whether BCG might alter those changes under controlled conditions.

The team vaccinated one group of mice at three months of age and gave saline to another. A separate comparison group consisted of age-matched mice without dementia that also received saline. Eight to nine months later, the researchers assessed brain features, gene expression, inflammation and memory. The behavioral assessment included a novel object recognition test, which measures whether mice recognize an object they have encountered before.

BCG-treated mice were about five times more likely to show reduced tau deposits than untreated animals. They were also four times less likely to show markers of sustained inflammation. The researchers interpreted the lower inflammatory signal as consistent with immune cells having responded to tau and cleared some tangles, although the study does not settle the precise sequence of events.

Immune changes accompanied behavioral gains

The gene-expression results offered another measure of the vaccine’s effect. Untreated mice showed activation of 716 genes associated with Alzheimer’s disease, cell death and neuroinflammation. After BCG treatment, all but nine of those genes were normalized, according to the study. Vaccinated mice also showed less evidence of brain atrophy and performed better at recognizing objects.

The team reported that BCG reduced phosphorylated tau levels and neuronal loss, while restoring glutamate levels in vivo. The treated mice also did better in maintaining body weight and survival. Taken together, the results suggest that the observed differences extended beyond a single measure of tau deposits. They do not, however, show that every effect arose through the same biological mechanism.

William Bishai, MD, PhD, the study’s senior and corresponding author and co-director of the Johns Hopkins Center for Tuberculosis Research, said the team is investigating how the response works. “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.”

Trained immunity describes changes in innate immune cells after an initial stimulus. Cells such as monocytes and macrophages can undergo epigenetic and metabolic reprogramming, potentially changing how they respond to a later challenge—even one unrelated to the first. This differs from the learned responses typically associated with adaptive immune cells such as T cells.

Bishai said myeloid cells in the brain and central nervous system may use information from BCG to respond to plaques and tangles. “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,” he said. The researchers are studying other features of trained immunity to clarify how the vaccine might affect tau pathology.

Human observations remain a research lead

The mouse experiment builds on observational studies that have linked certain vaccines with lower dementia incidence. Such studies can identify associations, but they are not designed to establish that a vaccine caused the difference. The researchers cited reports linking shingles vaccination with a 20% lower incidence of dementia, as well as studies associating BCG immunotherapy for non-muscle invasive bladder cancer with a 12% to 78% lower dementia risk over periods of three to 15 years.

Those human findings help explain why researchers are investigating BCG in the laboratory. They do not show that vaccination prevents dementia, and the range of reported BCG associations does not establish what effect, if any, would apply to a particular person. The mouse study adds a possible biological explanation to explore: trained immunity may affect how immune cells respond to disease-related tau.

The authors called their work the first study of BCG in a dementia mouse model with tau pathology and said the results support further basic research and large-scale prospective clinical trials. Earlier work in amyloid mouse models has also reported improved cognition after BCG, but those models represent disease processes centered on plaque formation. The current findings extend the investigation to tau and the possibility that immune cells contribute to clearing neurofibrillary tangles.

Co-author Barbara Slusher, PhD, a professor of neurology at Johns Hopkins University School of Medicine and director of the Johns Hopkins Drug Discovery program, described the work as “translational science working in reverse”—starting with an observation in people and returning to laboratory studies to examine why it might occur.

Slusher said researchers need a clearer understanding of the underlying biology before they can determine who might benefit, when treatment would need to be given or whether the effect can be reproduced safely in people at risk of dementia. She added that identifying protective immune changes could help researchers develop more targeted approaches to Alzheimer’s prevention.

For now, BCG’s relevance to dementia rests on an encouraging animal study and human associations that still require causal testing. The next step is to pin down which immune changes accompany the reduction in tau pathology, then determine whether those changes can be reproduced in people.

The research paper, “BCG vaccination mitigates tau pathology and restores cognitive functions in PS19 mice,” was published in Science Advances.

The original report, BCG Vaccine-Induced Trained Immunity May Help Protect Against Dementia, appeared in GEN - Genetic Engineering and Biotechnology News.