Recent studies suggest that a vaccine discovered a century ago could provide a cheap and effective way to boost the immune system to protect people from Alzheimer's disease. In addition, it seems to have a positive effect in the treatment of bladder cancer. The idea may seem far-fetched, but decades of research show that the BCG vaccine can have surprising and far-reaching benefits that go far beyond its original purpose, reports The Guardian.
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How the BCG vaccine was discovered
Scientific breakthroughs can come from the strangest places. In the early 1900s, in France, general practitioner Albert Calmette and veterinarian Camille Guérin sought to discover the mode of transmission of bovine tuberculosis. To do this, they first had to find a way to grow the bacteria. Sliced potatoes – treated with ox bile and glycerin – proved to be the perfect medium. However, as the bacteria evolved, Calmette and Guérin were surprised to find that each generation lost some of their virulence. Animals infected with the microbe (raised through several generations of their culture) did not get sick, but were protected against wild tuberculosis.
In 1921, the two 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, which saved millions of lives.
10 million new cases of Alzheimer's per year globally
According to the World Health Organization, 55 million people currently suffer from dementia, with approximately 10 million new cases each year. Alzheimer's disease is by far the most common form, accounting for approximately 60%-70% of cases of neuronal degeneration. Alzheimer's is characterized by clumps of a protein called amyloid beta that build up in the brain, killing neurons and destroying synaptic connections between cells.
What causes beta amyloid plaques has been a mystery, but more research now points to problems with the immune system. When we are young, our body's defenses can prevent bacteria, viruses or fungi from reaching the brain. However, as we age, they become less effective, which can allow microbes to make their way into our neural tissue.
According to this theory, amyloid beta is produced to kill these invaders as a short-term defense against infection. If the brain's own immune cells – known as microglia – were functioning optimally, they could remove the protein once the threat has passed. But in many cases of Alzheimer's disease, they appear to malfunction, triggering widespread inflammation that leads to further neuronal “carnage.”
If this theory is correct, attempts to boost the overall functioning of the immune system could prevent the development of the disease.
New approaches in medicine
Certainly, new approaches are needed in terms of treating Alzheimer's disease. After decades of research into ways to eliminate plaque, only two new drugs have been approved by the US Food and Drug Administration. Both rely on antibodies that bind to amyloid beta proteins, triggering an immune response that clears them from the brain. This appears to slow disease progression in some patients, but improvement in overall quality of life is often limited.
The main drawback is that these anti-amyloid antibodies have an extremely high cost. “The cost of treatment is likely to lead to a huge gap in health equity in low-income countries,” says Marc Weinberg, who does Alzheimer's research at Massachusetts General Hospital in Boston.
In this context, the researchers' attention turned to the tuberculosis vaccine. Although the idea may seem far-fetched, decades of research show that BCG can have surprising and far-reaching benefits that go far beyond its original purpose. As well as protecting people against tuberculosis, it also appears to reduce the risk of other serious infections.
BCG is also used as a standard treatment for forms of bladder cancer. Once the attenuated bacteria have reached the organ, they trigger the immune system to eliminate tumors where they previously went unnoticed. “It can lead to remarkable healings,” says Professor Richard Lathe, a molecular biologist at the University of Edinburgh.
BCG causes “trained immunity”
These remarkable effects are thought to occur through a process called “trained immunity.” After a person has received BCG, changes can be seen in the expression of genes associated with the production of cytokines – small molecules that can activate other defense systems, including white blood cells. As a result, the body can respond more effectively to a threat, whether it's a virus or bacteria that enters the body, or a mutated cell that threatens to grow out of control. “It can be compared to upgrading a building's security system to be more responsive and effective, not just against known threats, but against any potential intruders,” says Marc Weinberg.
There are good reasons to believe that trained immunity could reduce the risk of Alzheimer's. By strengthening the body's defenses, it could help keep pathogens at bay before they reach the brain. It could also cause the brain's own immune cells to more effectively eliminate amyloid beta proteins without triggering an attack by them on healthy neural tissue.
Animal studies provide some tentative evidence. For example, laboratory mice immunized with BCG showed a substantial reduction in brain inflammation. This results in significantly better thinking, where other mice of the same age begin to show a steady decline in memory and learning. But would the same be true of humans?
In this type of epidemiological research, there may be a less obvious factor that is not properly taken into account.
To find out, Ofer Gofrit, of the Hadassah-Hebrew University Medical Center in Jerusalem, and his colleagues collected data on 1,371 people who had or had not received BCG as part of their bladder cancer treatment. They found that only 2.4 percent of BCG-treated patients developed Alzheimer's over the next eight years, compared with 8.9 percent of those who did not receive the vaccine.
Even the simple delay of the disease would be a success
The results were published in 2019 and since then other researchers have started to keep statistics, to see if this theory is confirmed or not. Marc Weinberg's team, for example, examined the records of about 6,500 bladder cancer patients in Massachusetts. In particular, they ensured that the sample of BCG recipients and non-BCG recipients was carefully matched for age, sex, ethnicity, and medical history. It turned out that people who received the vaccine were much less likely to develop dementia.
The exact level of protection varies from study to study, with a recent meta-analysis showing an average risk reduction of 45%. If this can be proven through further studies, the implications would be huge. “Simply delaying the onset of Alzheimer's disease by a few years would mean an enormous amount in terms of suffering…”, says Professor Charles Greenblatt of the Hebrew University of Jerusalem, who co-authored Gofrit's original paper.
At the moment, the researchers' skepticism is absolutely necessary, because all the existing work has examined patients with bladder cancer, but so far there is little data on the general population. An obvious strategy might be to compare people who got the BCG vaccine in childhood with those who didn't, but the effects of BCG might wear off over decades, long before most people are at risk of getting it. develop Alzheimer's.
Decisive evidence would come from a randomized controlled trial in which patients are assigned either the active treatment or a placebo. Because dementia develops very slowly, it will take years to collect enough data to show that BCG provides the expected protection against full-blown Alzheimer's disease compared to a placebo.
The BCG vaccine would be the cheapest treatment against Alzheimer's disease
Meanwhile, scientists have begun to examine certain biomarkers that show the early stages of the 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 later diagnosis with a reasonable accuracy.
A pilot study by Coad Thomas Dow of the University of Wisconsin-Madison and colleagues suggests that BCG injections can effectively reduce plasma amyloid levels, particularly among those who carry the genetic variants associated with a risk greater than Alzheimer's. Although the sample was small — only 49 participants in total — it bolstered hopes that immune training will be an effective strategy for fighting the disease. “These results were encouraging,” says Marc Weinberg, who was not involved in this study.
Weinberg has his own reasons for optimism. Working with Drs Steven Arnold and Denise Faustman, he collected samples of cerebrospinal fluid from people who did and did not receive the vaccine. The goal was to see if the effects of trained immunity could reach the brain, and that's exactly what they found. “The response to pathogens is stronger in certain specific populations of these immune cells after BCG vaccination,”
says Marc Weinberg.
We can only hope that these early results will inspire further testing. Because. as Marc Weinberg says, “BCG vaccine is safe and accessible worldwide;, it is incredibly cheap compared to the other options. Even though it only provides very little protection, BCG wins the cost-effectiveness contest by a wide margin.”
If these preliminary results are confirmed in clinical trials, it could be one of the cheapest and most effective weapons in our fight against Alzheimer's and degenerative diseases in general.
