Early study suggests TB vaccine may retrain brain immunity to fight Alzheimer's

As people age, the immune system enters a state of chronic, low-grade inflammation known as “inflammaging.” In the brain, this condition is particularly harmful. Immune cells that normally clear away amyloid-beta — a protein that clumps to form the plaques characteristic of Alzheimer’s disease — become dysfunctional, fuelling the neuroinflammation that drives the disease.

Given this, a vaccine that stimulates the immune system might seem an unlikely candidate for treating Alzheimer’s. Yet a new study, published in the journal Communications Medicine, suggests that the century-old tuberculosis vaccine Bacillus Calmette-Guérin (BCG) may do the opposite. Instead of broadly boosting immunity, it appears to retrain innate immune cells within the ageing brain.

The study is based on the concept of trained immunity, where certain vaccines give innate immune cells a long-lasting memory, allowing them to respond more effectively to unrelated threats. Unlike antibodies, which target specific germs, trained immunity makes the innate immune system more responsive to a wide range of dangers. Clinicians have also 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 Massachusetts General Hospital in the United States enrolled 23 older adults, roughly half of whom had cerebrospinal fluid biomarkers indicative of Alzheimer’s disease. Participants received two doses of BCG a month apart, and the researchers tracked their blood and cerebrospinal fluid over the following year.

Measuring such fluid is challenging. “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.

Despite the small number of cells, the team found that monocytes — the predominant immune cells in the cerebrospinal fluid in this study — switched on genes linked to a faster, more alert immune response, mirroring changes seen 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, said Soumen Basak, an immunologist at the National Institute of Immunology in Delhi.

Notably, when the team reexposed these cells to BCG itself in the lab, they did not respond more strongly than before. But they did respond more strongly to an unrelated bacterial molecule called lipopolysaccharide (LPS), suggesting the vaccine had put the 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. Dr. Basak suggested the brain may similarly shape how these cells respond.

Whether the change in immune cell behaviour 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 noted, however, that this is descriptive rather than proof of clearance.

In participants with established Alzheimer’s, this change did not 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 clearance even if immune cells had been retrained.

The study is preliminary and based on a small group. Larger trials are needed to determine whether BCG could offer a meaningful therapeutic approach for Alzheimer’s at early stages, and whether it might help those already affected.