Recent studies have suggested that the BCG jab – the tuberculosis vaccine that has saved millions of lives since discovery a century ago – could provide a cheap, effective way of boosting the immune system to protect people from developing Alzheimer’s disease.
In the early 1900s, in France, doctor Albert Calmette and veterinarian Camille Guérin aimed to discover how bovine tuberculosis was transmitted. But 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.
Now, a string of intriguing studies suggests 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, reports The Guardian.
Around 55m people now have have dementia, with about 10m new cases each year.
Alzheimer’s is the most common form, accounting for about 60%-70% of cases, and characterised by clumps of amyloid beta protein 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.
As youngsters, our body’s defences can prevent bacteria, viruses or fungi from reaching the brain. As we age, 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 – microglia – were working optimally, they could clear away the protein once the threat has passed. But in many cases of Alzheimer’s, they seem to malfunction, triggering widespread inflammation, leading to further neural carnage.
Much 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 needed. After decades of research on ways to clear the plaques, only two new drugs have been approved, both 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 are also expensive, “which 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.
Existing vaccines like BCG might offer an alternative solution. Decades of research show BCG can have wide-ranging benefits extending beyond its original purpose.
Besides protecting people from TB, it seems to reduce the risk of many other infections: in a recent clinical trial, BCG halved the odds of developing a respiratory infection over the next 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.
These 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.
So 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.
There are good reasons to believe 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.
Just 2.4% of the patients treated with BCG developed Alzheimer’s over the next eight years, compared with 8.9% of those not given the vaccine.
Since then, other researchers have replicated the findings. Weinstein’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.
Plenty of caution is necessary. Existing papers have all examined patients with bladder cancer, but 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.
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.
Meanwhile, scientists have started examining certain biomarkers that show the early stages of disease. Until recently, this was 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.
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, whicj is exactly what they found. “The response to pathogens is more robust in specific populations of these immune cells after BCG vaccination,” says Weinberg..
“The BCG vaccine is safe and globally accessible,” he adds. It is also cheap compared with the other options, and even it confers just a tiny bit of protection, “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.
Study details
The role of Bacillus Calmette-Guérin administration on the risk of dementia in bladder cancer patients: a systematic review and meta-analysis
Chao Han1 Juan Wang, Ya-Li Chen, Cui-Ping Guan, Yan-An Zhang, Mao Shui-Wang.
Published in Frontiers on 24 August 2023
Background
Previous cohort studies have found an association between Bacillus Calmette–Guérin (BCG) administration and incident dementia. In the systematic review and meta-analysis, we aimed to summarize the current evidence of the effect of BCG use on the risk of developing dementia.
Methods
We searched six databases until 20 May 2023 for studies investigating the risk of dementia and BCG administration. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Meta-regression, subgroup, and sensitivity analysis were conducted as well.
Results
Of the 4,043 records initially evaluated, five articles were included for final analysis, with a total of 45,407 bladder cancer (BC) patients. All five studies were evaluated and rated as with high quality, and a low possibility of publication bias was indicated. A significant association between BCG and the incidence of dementia in BC patients was found in all five studies. Although a high heterogeneity (I2 = 84.5%, p < 0.001) was observed, the pooled HR was 0.55 (0.42–0.73), indicating that BCG exposure or treatment reduced the risk of incident dementia by 45%. Moreover, the sensitivity analysis showed good robustness of the overall effect with no serious publication bias.
Conclusion
BCG administration is associated with a significantly lower risk of developing dementia. However, an epidemiological cohort is needed to establish a relationship between BCG use and incident dementia in the normal population. Once the relationship is confirmed, more people may benefit from the association.
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