Scientific discoveries can emerge from the strangest places. In early 1900s France, the doctor Albert Calmette and the veterinarian Camille Guérin aimed to discover how bovine tuberculosis was transmitted. To do so, they first had to find a way of cultivating the bacteria. Sliced potatoes – cooked with ox bile and glycerine – proved to be the perfect medium.
As the bacteria grew, however, Calmette and Guérin were surprised to find that each generation lost some of its virulence. Animals infected with the microbe (grown through many generations of their culture) no longer became sick but were protected from wild TB. In 1921, the pair tested this potential vaccine on their first human patient – a baby whose mother had just died of the disease. It worked, and the result was the Bacille Calmette-Guérin (BCG) vaccine that has saved millions of lives.
Calmette and Guérin could have never imagined that their research would inspire scientists investigating an entirely different kind of disease more than a century later. Yet that is exactly what is happening, with a string of intriguing studies suggesting that BCG can protect people from developing Alzheimer’s disease.
If these preliminary results bear out in clinical trials, it could be one of the cheapest and most effective weapons in our fight against dementia.
According to the World Health Organization, 55 million people now have dementia, with about 10 million new cases each year. Alzheimer’s disease is by far the most common form, accounting for about 60%-70% of cases. It is characterised by clumps of a protein called amyloid beta that accumulate within the brain, killing neurons and destroying the synaptic connections between the cells.
Exactly what causes the plaques to develop has been a mystery, but multiple lines of evidence implicate problems with the immune system. When we are young, our body’s defences can prevent bacteria, viruses or fungi from reaching the brain. As we get older, however, they become less efficient, which may allow microbes to work their way into our neural tissue. According to this theory, the amyloid beta is produced to kill those invaders as a short-term defence against infection. If the brain’s own immune cells – known as microglia – were working optimally, they could clear away the protein once the threat has passed. But in many cases of Alzheimer’s disease, they seem to malfunction, triggering widespread inflammation that leads to further neural carnage.
A wealth of evidence now supports this theory. Autopsies have revealed brains of people with Alzheimer’s are more likely to be home to common microbes such as the herpes simplex virus, the cause of cold sores. Crucially, these germs are often entrapped in the amyloid, which has been proven to have antimicrobial properties.
If this theory is correct, attempts to boost the immune system’s overall functioning could prevent the development of the disease.
New approaches are certainly needed. After decades of research on ways to clear the plaques, only two new drugs have been approved by the US Food and Drug Administration. Both are based on antibodies that bind to the amyloid beta proteins, triggering an immune response that clears them out of the brain. This appears to slow disease progression in some patients, but the improvement in overall quality of life is often limited.
Anti-amyloid antibodies also come with a hefty price tag. “The cost of treatment is likely to lead to an enormous health equity gap in lower-income countries,” says Marc Weinberg, who researches Alzheimer’s at Massachusetts general hospital in Boston. (He emphasises his opinions are personal and do not reflect those of his institution.)
Could existing vaccines such as BCG offer an alternative solution?
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The idea may sound far-fetched, but decades of research show that BCG can have surprising and wide-ranging benefits that go way beyond its original purpose. Besides protecting people from TB, it seems to reduce the risk of many other infections, for instance. In a recent clinical trial, BCG halved the odds of developing a respiratory infection over the following 12 months, compared with the people receiving a placebo.
BCG is also used as a standard treatment for forms of bladder cancer. Once the attenuated bacteria have been delivered to the organ, they trigger the immune system to remove the tumours, where previously they had passed below the radar. “It can result in remarkable disease-free recoveries,” says Prof Richard Lathe, a molecular biologist at Edinburgh University.
These remarkable effects are thought to emerge from a process called “trained immunity”. After an individual has received BCG, you can see changes in the expression of genes associated with the production of cytokines – small molecules that can kick our other defences, including white blood cells, into action. As a result, the body can respond more efficiently to a threat – be it a virus or bacteria entering the body, or a mutant cell that threatens to grow uncontrollably. “It can be likened to upgrading the security system of a building to be more responsive and efficient, not just against known threats but against any potential intruders,” says Weinberg.
There are good reasons to believe that trained immunity could reduce the risk of Alzheimer’s. By bolstering the body’s defences, it could help keep pathogens at bay before they reach the brain. It could also prompt the brain’s own immune cells to clear away the amyloid beta proteins more effectively, without causing friendly fire to healthy neural tissue.
Animal studies provide some tentative evidence. Laboratory mice immunised with BCG have reduced brain inflammation, for example. This results in notably better cognition, when other mice of the same age begin to show a steady decline in their memory and learning. But would the same be true of humans?
To find out, Ofer Gofrit of the Hadassah-Hebrew University Medical Centre in Jerusalem and his colleagues collected the data of 1,371 people who had or had not received BCG as part of their treatment for bladder cancer. They found that just 2.4% of the patients treated with BCG developed Alzheimer’s over the following eight years, compared with 8.9% of those not given the vaccine.
Since the results were published in 2019, other researchers have replicated the findings. Weinberg’s team, for instance, examined the records of about 6,500 bladder cancer patients in Massachusetts. Crucially, they ensured that the sample of those who had received BCG and those who hadn’t were carefully matched for age, gender, ethnicity and medical history. The people who had received the injection, it transpired, were considerably less likely to develop dementia.
The precise level of protection varies between studies, with a recent meta-analysis showing an average risk reduction of 45%. If this can be proven with further studies, the implications would be huge. “Simply delaying the development of Alzheimer’s by a couple of years would lead to tremendous savings – both in suffering and our money,” says Prof Charles Greenblatt of the Hebrew University of Jerusalem, who was a co-author of Gofrit’s original paper.
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Plenty of caution is necessary. The existing papers have all examined patients with bladder cancer, but as yet there is little data on the general population. One obvious strategy may be to compare people who have received the BCG vaccine during childhood with those who hadn’t, but the effects of BCG may dwindle over the decades – long before most people would be in danger of developing Alzheimer’s.
We can, however, examine the effects of other vaccines delivered in old age. With its live (but attenuated) bacteria, BCG is thought to provide the most potent immune training, but other vaccines may also stimulate the body’s defences. Consider the flu jab. Nicola Veronese of the University of Palermo in Italy and her colleagues recently analysed the results of nine studies, many of which controlled for lifestyle factors, including income, education, smoking, alcohol consumption and hypertension. The team found that the influenza vaccine was associated with a 29% reduced risk of dementia. “Two studies also showed an association between the number of doses, over previous years, and the incidence of dementia,” says Veronese.
Such studies still cannot prove causality. “In this kind of epidemiological research, it may be that there’s a confounding factor that’s lurking that isn’t properly accounted for,” says Jeffrey Lapides of Drexel University College of Medicine in Pennsylvania, though he agrees that the vaccine effects on dementia are plausible and deserve more research.
The clinching evidence would come from a randomised controlled trial in which patients are either assigned the active treatment or the placebo. Since dementia is very slow to develop, it will take years to collect enough data to prove that BCG – or any other vaccine – offers the expected protection from full-blown Alzheimer’s compared with a placebo.
In the meantime, scientists have started to examine certain biomarkers that show the early stages of disease. Until recently, this was extraordinarily difficult to do without expensive brain scans, but new experimental methods allow scientists to isolate and measure levels of amyloid beta proteins in blood plasma, which can predict a subsequent diagnosis with reasonable accuracy.
A pilot study by Coad Thomas Dow of the University of Wisconsin-Madison and his colleagues suggests that BCG injections can effectively reduce plasma amyloid levels, particularly among those carrying the gene variants associated with a higher risk of Alzheimer’s. Although the sample size was small – just 49 participants in total – it has bolstered hopes that immune training will be an effective strategy for fighting the disease. “These results were encouraging,” says Weinberg, who was not involved in the study.
Weinberg has his own grounds for optimism. Working with Dr Steven Arnold and Dr Denise Faustman, he has collected samples of the cerebrospinal fluid that washes around the central nervous system of people who have or have not received the vaccine. Their aim was to see whether the effects of trained immunity could reach the brain – and that is exactly what they found. “The response to pathogens is more robust in specific populations of these immune cells after BCG vaccination,” says Weinberg.
We can only hope that these early results will inspire further trials. For Weinberg, it’s simple. “The BCG vaccine is safe and globally accessible,” he says. It is also incredibly cheap compared with the other options, costing just a few pence a dose. Even if it confers just a tiny bit of protection, he says: “It wins the cost-effectiveness contest hands down.”
As Calmette and Guérin discovered with their potato slices more than a century ago, progress may come when you least expect it.
• This article was amended on 26 February 2024 to correct an instance of a misspelling of Marc Weinberg’s surname.
• The Expectation Effect: How Your Mindset Can Transform Your Life by David Robson is published by Canongate (£10.99). To support the Guardian and Observer order your copy at guardianbookshop.com. Delivery charges may apply
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