BOSTON — Steven Arnold, MD, of Massachusetts General Hospital, and co-authors published findings in Communications Medicine concerning two open-label clinical trials of the Bacillus Calmette-Guérin (BCG) vaccine. The findings indicate that BCG vaccination alters immune activity in cerebrospinal fluid and is associated with changes in Alzheimer's biomarkers in older adults who did not have baseline Alzheimer's pathology.

The study involved two one-year, open-label clinical trials with adults aged 55 and older at a single center. One trial included 12 participants without Alzheimer's-related pathology, while the other involved 11 people with Alzheimer's pathology and mild cognitive impairment or mild-to-moderate Alzheimer's disease. Participants received two intradermal BCG vaccinations one month apart.

In participants without Alzheimer's-related pathology at baseline, BCG vaccination was associated with decreased amyloid-beta levels in cerebrospinal fluid and increased amyloid levels in blood. This shift in amyloid-beta levels was not observed in participants who already had Alzheimer's pathology. The vaccine induced persistent, trained immunity-like changes in cerebrospinal fluid, including enhanced innate immune responsiveness.

This heightened immune responsiveness was not accompanied by an increase in inflammatory markers. Dr. Arnold stated, "This pilot study provides early human evidence that BCG vaccination can alter immune activity not only in the blood, but also in immune cells found in the cerebrospinal fluid, the fluid surrounding the brain and spinal cord." He added, "That is a key step in moving from epidemiologic observations toward a plausible biological mechanism."

One non-serious case of injection site dermatitis occurred during the study. No other adverse events were attributed to BCG. Dr. Arnold noted, "This study was not designed to show that BCG prevents or treats Alzheimer's disease. It was small, open-label, and designed to look at safety and biological mechanisms. But it gives us a biologically grounded rationale for testing whether immune training with BCG could be useful as an early prevention strategy for Alzheimer's disease."

Pierre Tariot, MD, of the Banner Alzheimer's Institute, commented that "Mechanistic studies such as this one reveal two sequential phases of immune reprogramming suggesting durable, disease-modifying modulation of the aging neuroimmune environment." Marc Weinberg, MD, PhD, a co-first author, stated that vaccines have traditionally been viewed through the lens of infectious disease prevention. He added, "Although more research is needed, these findings suggest they may also influence biological processes involved in brain aging and neurodegenerative disease."

Dr. Arnold indicated that the next step is a large, randomized, controlled prevention trial to determine if BCG can reduce the risk of cognitive decline or Alzheimer's disease and identify which older adults might benefit most. A group of investigators across the U.S. has submitted an application to the NIH for such a trial. Arnold said, "If funded, the goal would be to test BCG in a real-world prevention framework, with careful safety monitoring and clinically meaningful outcomes, including cognitive trajectories and Alzheimer's-related biomarkers."

Why It Matters

The BCG vaccine has been used against tuberculosis since the 1920s and was approved by the U.S. Food and Drug Administration in 1990 to treat bladder cancer. It is known to induce "trained immunity," a long-lasting reprogramming of innate immune responses. Retrospective studies have linked BCG treatment for non-muscle-invasive bladder cancer to reduced risks of Alzheimer's disease and other dementias.

The current study's findings suggest that BCG vaccination may have an impact on Alzheimer's biomarkers, particularly in individuals without pre-existing Alzheimer's pathology. The research did not examine the effect of BCG vaccination applied during childhood, a common practice in sub-Saharan Africa, Southeast Asia, and parts of Eastern Europe.