Tuberculosis Vaccine May Reshape Brain Immunity and Alter Alzheimer Biomarkers, Early Trial Data Show

New findings from Mass General Brigham investigators suggest that the century-old Bacillus Calmette-Guérin (BCG) vaccine, which has long been used to prevent tuberculosis, may do more than train peripheral immunity—it may also reprogram immune activity within the central nervous system (CNS) and shift biomarkers tied to Alzheimer disease (AD). The results, which were published in Communications Medicine, offer a possible biological explanation for previous epidemiological associations between BCG exposure and reduced dementia risk.^1,2

Study Design

Researchers conducted 2 related 1-year, open-label clinical trials in adults aged 55 years and older. Twenty-three total participants were enrolled, including 12 without AD-related pathology and 11 with biomarker-confirmed AD pathology. All participants received 2 intradermal BCG vaccinations 1 month apart, with blood and cerebrospinal fluid (CSF) collected at baseline, 3 months, 6 months (blood only), and 12 months. Investigators used cytokine assays and single-cell RNA sequencing to characterize immune responses in both compartments, an approach that allowed them to directly compare peripheral and CNS-associated immune activity within the same individuals over time.¹

Trained Immunity Extends to the CNS

BCG is a well-established inducer of "trained immunity," a form of innate immune memory in which prior exposure heightens responsiveness to unrelated future challenges. This phenomenon has been documented extensively in blood, but its presence within the CNS had not been established in humans. In this trial, CSF monocytes exhibited sustained, trained immunity-like transcriptional responses to lipopolysaccharide stimulation through 12 months, with upregulation of genes tied to cytokine signaling and metabolic reprogramming. Notably, this heightened responsiveness was not accompanied by elevated baseline inflammatory markers—an important distinction, since chronic neuroinflammation is itself considered a driver of neurodegeneration.^1,2

Interestingly, CSF monocytes did not respond directly to restimulation with heat-killed BCG itself, even though they responded robustly to other stimuli. Researchers noted this pattern points toward secondary mechanisms, such as trained myeloid precursors migrating into the CNS or epigenetic reprogramming of resident CNS immune cells, rather than direct antigen recall.¹

Divergent Amyloid-Beta Dynamics by Disease Stage

Among participants without AD pathology, BCG vaccination was associated with a significant decline in CSF amyloid-β 42 (Aβ42) alongside a corresponding rise in plasma Aβ42, producing a 38% reduction in the CSF-to-plasma Aβ42 ratio over 12 months. This pattern was not observed in participants with existing AD pathology, suggesting that timing of intervention relative to disease onset may influence whether BCG affects amyloid clearance dynamics. The study authors noted this divergence aligns with the broader understanding that Aβ accumulation in established AD reflects impaired clearance rather than increased production and cited a small prior study that similarly found increased plasma Aβ42/40 ratios following BCG in healthy, younger adults.^1,2

Peripheral and CNS cytokine responses also diverged by disease status. In plasma, participants with AD showed a more pronounced and sustained proinflammatory cytokine response (including IL-1β, IL-6, and TNF-α) compared with those without. Within the CSF, however, both groups showed a shared, immunoregulatory trajectory, with interferon-gamma and IL-2 declining by 12 months regardless of AD status.¹

Safety and Context

BCG was well tolerated across both trials, with no unexpected safety signals. One case of nonserious injection site dermatitis was reported, and all participants developed the expected local BCG scar. These findings build on a growing body of evidence linking BCG to reduced dementia risk, including a 2023 cohort study of more than 6400 patients with non–muscle-invasive bladder cancer, which found intravesical BCG treatment was associated with a lower risk of AD and related dementias. With an estimated 7.4 million Americans currently living with Alzheimer dementia, and that number projected to nearly double by 2060 without new interventions, researchers say identifying modifiable, early biological targets remains a public health priority.^1,3,4

Clinical Takeaway for Pharmacists

The study authors were clear that these findings are hypothesis-generating rather than practice-changing. Senior author Steven Arnold, MD, managing director of the Interdisciplinary Brain Center at Mass General Brigham Neuroscience Institute, noted that larger, placebo-controlled trials are needed, particularly to evaluate whether BCG could play a role in prevention before significant AD pathology develops.²

"Vaccines have traditionally been viewed through the lens of infectious disease prevention,” co-first author Marc Weinberg, MD, PhD, who contributed to the study while working as a research scientist at Mass General Brigham, said. “Although more research is needed, these findings suggest they may also influence biological processes involved in brain aging and neurodegenerative disease."²

For pharmacists, the study underscores an emerging area of interest at the intersection of vaccinology and neurodegenerative disease—one worth monitoring as controlled trials progress, but not yet one with implications for current counseling or off-label use.^1,2

REFERENCES

1. Weinberg MS, Kodali MC, Li Z, et al. Bacillus Calmette-Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer's biomarkers: results from two open-label clinical trials. Commun Med. 2026;6(1):358. doi:10.1038/s43856-026-01691-7

2. Tuberculosis vaccine changes brain's immune environment and Alzheimer's biomarkers in older adults. News release. EurekAlert! July 6, 2026. Accessed July 24, 2026. https://www.eurekalert.org/news-releases/1134103

3. 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. doi:10.1001/jamanetworkopen.2023.14336

4. 2026 Alzheimer's disease facts and figures. Alzheimers Dement. 2026;22:e71345. doi:10.1002/alz.71345