As the immune system ages, it enters a state of chronic, low-grade inflammation called ‘inflammaging’.
In the brain, inflammaging is especially damaging. Immune cells that normally clear toxic amyloid-beta, a protein that can clump together to form the plaques characteristic of Alzheimer’s disease, instead become dysfunctional, fuelling the neuroinflammation that drives the disease.
So a vaccine that stimulates the immune system would seem an unlikely treatment for a disease driven by brain inflammation. But a new study in Communications Medicine suggests the century-old tuberculosis vaccine Bacillus Calmette-Guérin (BCG) does the opposite: rather than boosting immunity, it retrains innate immune cells within the ageing brain.
Training the immune system
The study is based on trained immunity, a phenomenon in which certain vaccines give innate immune cells a long-lasting memory, making them more effective against unrelated threats. Unlike antibodies, which recognise specific germs, trained immunity makes the innate immune system respond more effectively to many different threats. Clinicians have also long observed that bladder cancer patients treated with BCG have a lower incidence of dementia.
To test whether this immune training extends to the central nervous system, researchers at the Massachusetts General Hospital, U.S., enrolled 23 older adults, roughly half with and half without cerebrospinal fluid biomarkers of Alzheimer’s disease. Participants received two BCG doses a month apart and researchers tracked blood and the fluid over the following year.
Measuring this fluid is hard.
“From a 10-ml blood draw, you get about 10 million immune cells. During a lumbar puncture, you get about 10,000,” said Mahesh Chandra Kodali, a neuroscientist and study co-author at Massachusetts General Hospital.
But even with so few cells, the team found that monocytes — the predominant immune cells in cerebrospinal fluid in the study — switched on genes linked to a faster, more alert immune response, mirroring similar changes in the bloodstream.
“The findings strikingly reveal that trained immunity-like responses can occur within” the central nervous system, which is normally shielded from much of the body’s immune activity, Soumen Basak, an immunologist at the National Institute of Immunology, Delhi, said.
Notably, when the team reexposed these cells to BCG itself in the lab, they didn’t respond more strongly than before. But they did respond more strongly to an unrelated bacterial molecule called lipopolysaccharide (LPS) — suggesting the vaccine had put cells on general alert, rather than teaching them to recognise BCG alone, Dr. Kodali said.
Immune cells respond differently depending on the tissue they inhabit. Cells in the liver, for example, react differently to the same signal than similar cells in the lungs. So Dr. Basak suggested the brain may similarly shape how these cells respond.
This illustration made available by the National Institute on Ageing/National Institutes of Health depicts cells in an Alzheimer’s affected brain, with abnormal levels of the beta-amyloid protein clumping together to form plaques (brown) that collect between neurons and disrupt cell function.
| Photo Credit:
AP
Race against time
Whether this change in the way immune cells respond actually helps clear amyloid plaques from the brain is a separate question — and here the data suggest a race against time.
In participants without established Alzheimer’s, the results were promising. Amyloid levels fell in the cerebrospinal fluid and rose in the blood over the year — a pattern consistent with retrained immune cells helping move amyloid out of the brain and into the body. The authors did say this is descriptive rather than proof of clearance.
However, in participants with established Alzheimer’s, this change didn’t materialise. Dr. Kodali attributed this to the brain’s “ongoing inflammatory milieu and … dementia-related cascades,” referring to an environment where an already overwhelmed immune system has little capacity to respond. A damaged blood-brain barrier or dense amyloid plaques could also impede amyloid clearance even if immune cells had been retrained.
“This somewhat dents the therapeutic appeal of BCG in Alzheimer’s, while supporting its plausible utility as a preventive measure,” Dr. Basak said.
Resolving the paradox
In blood plasma, the vaccine triggered the expected sustained rise in inflammatory signalling proteins, especially in Alzheimer’s patients. But across the blood-brain barrier, which normally keeps the brain’s immune environment separate from the rest of the body, the cerebrospinal fluid changed into a calming, regulatory state in everyone, with no sign of runaway neuroinflammation.
As Dr. Kodali put it, the trial was designed to understand the biology of BCG’s effects, not to test whether it treats or prevents Alzheimer’s.
With just 23 participants split into two groups, the study was too small to draw firm conclusions.
The study also lacked a placebo group, so it’s impossible to rule out other explanations for the changes observed. Cognitive scores barely moved either way — unsurprising, Dr. Kodali said, since “dementia itself occurs over a period of several years,” which is too long for a one-year study to capture.
That said, a different Massachusetts General Hospital trial may offer a clue to what a longer timeline could reveal. Dr. Kodali pointed to work by his colleague Denise Faustman, who has followed BCG-vaccinated type I diabetes patients for over five years and has recorded early improvements in a key Alzheimer’s linked marker.
Dr. Kodali said this is consistent with a broader pattern in BCG research: the vaccine’s effects rely on slow chemical modifications that influence how genes are switched on or off, and which may take longer than a year to fully show up.
Clinical effects
Modern anti-amyloid drugs are expensive, Dr. Kodali said, whereas BCG is cheap and has decades of safety data behind it. That’s part of why the Banner Alzheimer’s Institute has submitted a roughly $200-million grant application to fund a large, randomised trial testing BCG as an Alzheimer’s preventive, he said.
Dr. Basak cautioned that any conclusions about the vaccine’s real-world relevance to disease will have to wait for such a trial. However, he also said the study points to the patterns of gene activity inside the brain’s own immune cells to be a promising new target for future therapies, potentially reaching beyond Alzheimer’s to other neurodegenerative diseases driven by inflammation.
Anirban Mukhopadhyay is a geneticist by training and science communicator from New Delhi.
Published – August 13, 2026 09:15 am IST
