- In older adults, the BCG vaccine may enhance the responsiveness of immune cells in the cerebrospinal fluid and blood, suggesting it may strengthen immune function without triggering harmful inflammation.
- Among those without evidence of Alzheimer’s disease, beta-amyloid levels decreased in cerebrospinal fluid and increased in the bloodstream, which may indicate improved clearance of beta-amyloid from the brain.
- However, the vaccine did not produce similar effects in those who already had biomarker evidence of Alzheimer’s disease, suggesting BCG may be more effective before significant disease develops.
- This small, open-label study provides a possible explanation for previous links between BCG and Alzheimer’s risk, but larger trials are still necessary.
In recent years, researchers have become increasingly interested in its “off-target” effects, which may extend beyond protection against TB.
Previous research suggests that BCG may strengthen the body’s broader immune response, known as trained immunity.
Most research has focused on immune changes in the bloodstream, while it remains unclear whether BCG can also influence immune cells within the central nervous system (CNS).
Now, a small, year-long clinical study suggests the BCG vaccine may alter immune activity around the brain and change levels of a protein closely associated with Alzheimer’s disease in older adults without evidence of the condition.
The findings, published in
In the small study, researchers from Mass General Brigham followed 23 adults aged 55 years and older over a 12-month period after they received BCG vaccination.
The participants were divided into two groups: 12 participants without evidence of Alzheimer’s disease pathology and 11 participants with biomarkers indicating Alzheimer’s pathology.
The study was open-label, meaning both researchers and participants knew the vaccine had been administered. There was also no placebo comparison group.
Throughout the study, researchers collected blood samples and cerebrospinal fluid (CSF) to assess changes in immune activity and Alzheimer’s-related biomarkers.
A key finding from the study suggests that BCG may increase the responsiveness of immune cells in both the blood and cerebrospinal fluid when exposed to subsequent immune challenges.
Importantly, this heightened immune activity did not coincide with increased inflammatory markers.
Speaking to Medical News Today, co-first author Marc Weinberg, MD, PhD, who contributed to the study while working as a research scientist at Mass General Brigham, highlighted the enhanced immune response without increasing inflammation as a key finding.
“This distinction matters because chronic inflammation in the brain is already thought to be part of Alzheimer’s disease biology. Inflammation can be helpful when it is short-lived and appropriately targeted, but when inflammatory signaling stays switched on over time, it can damage tissue and may contribute to disease progression,” Weinberg told us.
“In this study, BCG appeared to make immune cells more responsive under challenged conditions, without producing evidence of sustained inflammatory activation in the cerebrospinal fluid. That is important because the goal is not to simply ‘rev up’ inflammation in the brain, but potentially to improve immune function in a way that is more controlled, reactive, and effective.”
– Marc Weinberg, MD, PhD
The researchers also observed changes in beta-amyloid levels after vaccination. Beta-amyloid describes protein fragments that can accumulate in the brain and directly contribute to cognitive decline and memory loss
Among participants without Alzheimer’s pathology, beta-amyloid levels declined in CSF while increasing in the bloodstream over the course of the study.
This pattern may reflect improved clearance of the protein from the CNS into the blood. However, the study was not designed to prove this mechanism directly.
“One possibility is that BCG may have a greater effect before Alzheimer’s-related changes are well established,” Weinberg explained to MNT. “In people without Alzheimer’s pathology, immune and clearance systems may still be flexible enough to respond to BCG-induced immune training.”
In contrast, those who already showed evidence of Alzheimer’s pathology did not experience similar biomarker changes.
“Once Alzheimer’s pathology is present, some of the processes that normally help regulate or clear beta-amyloid may already be impaired. If those pathways are damaged, saturated, or less adaptable, BCG may not produce the same measurable biomarker response. This will be an important question for larger placebo-controlled studies,” Weinberg noted.
This suggests that BCG may have greater effects before Alzheimer’s disease becomes established, potentially highlighting the importance of timing for any future preventive strategies.
“In participants without Alzheimer’s pathology, we observed lower beta-amyloid levels in the cerebrospinal fluid and higher levels in the blood after BCG vaccination. One possible interpretation is that BCG may influence how beta-amyloid is transported, cleared, or redistributed between the brain and the rest of the body,” Weinberg added.
“We need to be careful with that interpretation because we did not directly measure beta-amyloid clearance. We measured beta-amyloid levels in different compartments before and after BCG, so the findings suggest a possible effect on amyloid handling, but they do not prove exactly where the beta-amyloid went or whether brain amyloid burden was reduced,” he cautioned.
While the results are promising, the researchers emphasize that it is too early to consider BCG as a preventive treatment for Alzheimer’s disease.
For now, the study offers new insight into the complex relationship between the immune system and the brain and provides a foundation for future research into whether immune-based approaches could help preserve brain health as people age.
Additionally, the authors caution that the study was small and designed primarily to explore biological mechanisms rather than determine whether BCG reduces Alzheimer’s risk or improves cognitive function.
As the trial did not include a placebo group, it is also not possible to conclude that the observed changes were caused solely by the vaccine.
Thus, larger, randomized, placebo-controlled studies will be necessary to confirm the findings and determine whether these biological changes translate into meaningful clinical benefits.
“Trained immunity is a form of memory in the innate immune system, which is the part of the immune system that responds quickly and broadly to threats,” Weinberg told MNT.
“One way to think about it is like airport security after a credible alert: the system may become more aware and responsive to future concerns, without necessarily being in a constant state of alarm,” he illustrated.
“This may be important for brain health because immune function changes with age. The aging immune system can become less efficient at responding to harmful disease-related changes, while also becoming more prone to chronic, low-grade inflammation,” said Weinberg.
“Our hypothesis is that BCG may help reprogram innate immune cells, including immune cells connected to the central nervous system, so they are more responsive to disease-related changes, not only infections. This study provides early evidence that this kind of immune reprogramming can be detected in the central nervous system, which is an important step in testing that hypothesis.”
– Marc Weinberg, MD, PhD
