We are currently doing ongoing experiments to see if BCG may have a therapeutic effect when given after the onset of symptoms to reveal if the vaccine may have a therapeutic effect above and beyond the preventive effect observed in the recent paper.
Regarding the use of BCG and humans, my personal opinion is that the mechanism of dementia prevention by BCG is related to trained immunity with epigenetic and metabolomic reprogramming of myeloid and microglial cells. Trained immunity in humans has been shown to wane after about 12 months. While this is speculative and not proven, it may be that if BCG does have a future as a human dementia vaccine it will need to be given annually like seasonal flu vaccinations.
PT: What do you think is driving the reduction in tau deposits in treated mice?
Bishai: Our study showed that microglial cells in vaccinated, tauopathy-prone (PS19) mice showed a higher degree of phagocytic activity, and that they removed tau peptides from the extracellular space more rapidly than those from unvaccinated mice. Hence, we think that BCG-mediated stimulation microglial cells is a pivotal part of the mechanism by which the vaccine reduces tau neurofibrillary tangles.
PT: How did you determine that “trained immunity” is a likely mechanism rather than a general anti-inflammatory effect?
Bishai: In the present study we focused on whether BCG had efficacy for preventing tauopathy progression in the PS19 mice. But we still have a ways to go to nail down the specific mechanism.
We hypothesize that trained immunity is at play because there were a few clues in our study. First, we found that microglial cells from the brains of BCG vaccinated tauopathy-prone (PS19) mice had a metabolic shift toward glycolysis, which is one of the hallmarks of trained immunity. And a second clue was that we also observed a higher level of peripheral monocytes expressing a known trained immunity surface marker, CD80.
Our current studies are intended to better understand the precise cellular mechanisms responsible for the effect. One important characteristic of trained immunity we will look for is epigenetic reprogramming of myeloid and microglial cells with DNA demonstrating classic activation marks. These include the H3K4me3 and H3K27ac epigenetic marks.
PT: What role do myeloid cells in the brain appear to play in clearing tau tangles?
Bishai: CNS microglial cells are of myeloid origin. Our work showed that while both vaccinated and unvaccinated tauopathy-prone (PS19) mice have elevated levels of microglial cells in their brains compared to healthy control mice, BCG vaccination led to reduced levels of deleterious activation— or microgliosis—among these microglial cells. We were also able to show that isolated microglial cells from vaccinated mice showed higher levels of phagocytic activity and could specifically and engulf and remove tau peptides.
A second category of myeloid cells that we observed changes in were in CNS monocytes recruited from the periphery. Our work showed that brain monocyte recruitment occurred at a significantly higher levels in BCG vaccinated mice than in the unvaccinated animals. Although we have yet to prove this particular mechanism, it is possible that BCG-mediated recruitment of peripheral monocytes into the CNS significantly augments the ability of endogenous CNS microglial cells to remove tau neurofibrillary tangles.
PT: How do your tau model results compare with earlier BCG work in amyloid models?
Bishai: One of the reasons we focused our work on the mouse tauopathy model with PS19 mice was that, as you point out, there are prior studies of BCG in preventing amyloid-beta disease in a different line of transgenic mice including at least 3 studies from Chinese laboratories. To my knowledge, we are the first to look at BCG in dementia prevention using a tau mouse model.
Similar to our work, the amyloid-beta mouse models showed improvement in mouse performance in memory behavioral tests following BCG vaccination.
An important difference between the 2 models is that our work shows that BCG reduces the tau neurofibrillary tangled burden, whereas the amyloid-beta studies showed no change in CNS lesion burden with BCG. Another difference was that the amyloid-beta studies showed that BCG led to a higher level of anti-inflammatory cytokines. In contrast, our work identified brain reprogramming of microglial cells as showing the most significant change mediated by BCG vaccination.
PT: What questions need answering before BCG is tested in people at risk for dementia?
Bishai: BCG was first used in humans in 1921. It is thought to be the most widely used vaccine in human history.At least 340 million infants receive BCG annually and several hundred thousand adults are treated with BCG annually for bladder cancer. BCG is also well tolerated, and adverse events are generally mild and occur infrequently.
Not surprisingly, with this excellent safety record, BCG is often used in human studies assessing fundamental aspects of human immunology including trained immunity. There are also numerous human studies of BCG assessing its role in off-target diseases, such as type I diabetes, multiple sclerosis, and prevention of viral infections,
So, there are no real obstacles for prospective clinical trials in humans to assess the efficacy of BCG in dementia prevention. Indeed, one such study is ongoing in Israel. Moreover, there is a US-based consortium—which I pleased to be a member of—that has proposed a large prospective clinical trial to test the efficacy of BCG for the prevention of dementia in older, at-risk adults.
PT: What 1-2 items would you highlight for the practicing psychiatric clinician?
Bishai: My first point would be that our study adds to the growing evidence that commonly used vaccines may prevent dementia. My second point is that most of the vaccines associated with dementia prevention are already recommended for broad use in the United States population. However, BCG is unique in that United States, western Europe and other wealthy countries do not use it. Hence, should BCG ultimately be proven effective against dementia, it would offer unique prevention activity above and beyond what most of the population already gets from the other vaccines.
References
1. Weinberg MS, Zafar A, Magdamo C, et al. Association of BCG vaccine treatment with death and dementia in patients with non–muscle-invasive bladder cancer. JAMA Netw Open. 2023;6(5):e2314336.
2. Study advances mechanistic insight into tuberculosis vaccine’s link to reduced dementia risk. Press release. October 21, 2026. Accessed October 26, 2026. https://www.hopkinsmedicine.org/news/newsroom/news-releases/2026/10/study-advances-mechanistic-insight-into-link-between-tuberculosis-vaccine-and-dementia-risk-reduction