SScientific discoveries can come from the strangest places. In France in the early 1900s, physician Albert Calmette and veterinarian Camille Guerin sought to understand how bovine tuberculosis was transmitted. To do this, they first needed to find a way to culture the bacteria. It turns out that sliced potatoes cooked in ox bile and glycerin are the perfect medium.
But as the bacteria multiplied, Calmette and Guerin were surprised to find that they lost some of their virulence with each successive generation. Animals infected with this microorganism (grown in culture over many generations) no longer became sick and were protected from tuberculosis in the wild. In 1921, the two tested this potential vaccine on their first human patient, a baby whose mother had just died from the disease. It worked, and the result was the Bacillus Calmette-Guerin (BCG) vaccine, which has saved millions of lives.
Calmette and Guerin could never have imagined that their work would inspire scientists more than a century later studying a completely different type of disease. But that's exactly what is happening, with a series of interesting studies suggesting that BCG can protect people from developing Alzheimer's disease.
If these preliminary results are proven in clinical trials, they could become one of the cheapest and most effective weapons in the fight against dementia.
According to the World Health Organization, 55 million people currently have dementia, and approximately 10 million new cases occur each year. Alzheimer's disease is the most common form of the disease, accounting for approximately 60% to 70% of cases. The disease is characterized by clumps of a protein called amyloid beta that build up in the brain, killing neurons and destroying synaptic connections between cells.
The exact cause of plaque development remains a mystery, but multiple lines of evidence point to problems with the immune system. When we are young, our body's defenses can prevent bacteria, viruses, and fungi from reaching the brain. However, as we age, its efficiency decreases, potentially allowing microorganisms to invade 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, are functioning optimally, they may be able to remove the proteins after the threat has passed. However, in many cases of Alzheimer's disease, they appear to malfunction, causing widespread inflammation and further neuronal destruction.
A wealth of evidence now supports this theory. Autopsies have revealed that common microorganisms such as the herpes simplex virus, which causes cold sores, are more likely to be present in the brains of Alzheimer's patients. Importantly, these bacteria are often trapped in amyloid, which has been shown to have antimicrobial properties.
If this theory is correct, attempts to strengthen the immune system as a whole could prevent the onset of disease.
New approaches are certainly needed. After decades of research on how to remove plaque, he is the only new drug approved by the U.S. Food and Drug Administration. Both are based on antibodies that bind to amyloid beta protein, triggering an immune response that clears it from the brain. Although this appears to slow disease progression in some patients, there is often limited improvement in overall quality of life.
Anti-amyloid antibodies also come with a hefty price tag. “Low-income countries are likely to see large health disparities because of the cost of treatment,” said Mark Weinberg, an Alzheimer's disease researcher at Massachusetts General Hospital in Boston. (He emphasizes that his opinions are personal and do not reflect those of his institution.)
Could existing vaccines such as BCG offer an alternative solution?
THis ideas may sound far-fetched, but decades of research have shown that BCG has surprising and far-reaching benefits that go far beyond its original purpose. It not only protects people from tuberculosis, but also appears to reduce the risk of many other infectious diseases, for example. In a recent clinical trial, BCG cut the odds of developing a respiratory infection in half over the next 12 months compared to people who received a placebo.
BCG is also used as a standard treatment for bladder cancer. When the attenuated bacteria reach an organ, the immune system kicks in and eliminates the tumor that previously flew under the radar. Professor Richard Reiss, a molecular biologist at the University of Edinburgh, said: “This could lead to an amazing disease-free recovery.”
These remarkable effects are thought to result from a process called “trained immunity.” Changes in the expression of genes related to cytokine production can be seen in people who have received BCG. Cytokines are small molecules that can activate other defenses, including white blood cells. As a result, the body is able to respond more efficiently to threats such as viruses and bacteria that enter the body, or mutated cells that may grow out of control. “This can be likened to upgrading a building's security system to be more responsive and efficient against known threats as well as potential intruders,” Weinberg said. says.
There is good reason to believe that a trained immune system can reduce the risk of Alzheimer's disease. By strengthening the body's defenses, researchers may be able to ward off pathogens before they reach the brain. It may also encourage the brain's own immune cells to clear amyloid beta protein more effectively, without causing friendly fire to healthy nerve tissue.
Animal studies provide some preliminary evidence. For example, laboratory mice immunized with BCG had reduced brain inflammation. This resulted in a significant increase in cognition at a time when other mice of the same age had begun to show a steady decline in memory and learning. But can the same be said of humans?
To find out, Ofer Goffrit of Hadassah Hebrew University Medical Center in Jerusalem and his colleagues collected data on 1,371 people who did and did not receive BCG as part of their bladder cancer treatment. Researchers found that only 2.4% of patients treated with BCG developed Alzheimer's disease over the next eight years, compared to 8.9% of patients who did not receive the vaccine. .
Since the results were published in 2019, other researchers have replicated them. For example, Weinstein's team looked at the records of about 6,500 bladder cancer patients in Massachusetts. Importantly, we ensured that the samples of those who received BCG and those who did not were carefully matched for age, gender, ethnicity, and medical history. It turns out that people who received the shot were significantly less likely to develop dementia.
The exact level of protection varies between studies, but a recent meta-analysis shows an average reduction in risk of 45%. If further research proves this, the impact would be huge. “Delaying the onset of Alzheimer's disease by just a few years would lead to huge savings in both suffering and our money,” said Charles Greenblatt of the Hebrew University of Jerusalem, co-author of Goffrit's original paper. says the professor.
PGreat care is required. All existing papers have investigated patients with bladder cancer, but there is still little data on the general population. One obvious strategy might be to compare people who received their BCG vaccine in childhood with those who didn't, but the effects of BCG are unlikely to put most people at risk of developing Alzheimer's disease. It can decline over decades, long before exposure.
However, we can study the effectiveness of other vaccines given to older people. BCG, which uses live (but attenuated) bacteria, is thought to provide the most powerful immune training, but other vaccines can also stimulate the body's defenses. Consider the flu jab. Nicola Veronese and colleagues at the University of Palermo in Italy recently analyzed the results of nine studies, many of which controlled for lifestyle factors such as income, education, smoking, alcohol intake and high blood pressure. The research team found that the influenza vaccine reduced the risk of dementia by 29%. “Two studies also showed an association between the number of doses given over the past few years and the incidence of dementia,” Veronese said.
Such studies have still not been able to prove causation. “In these types of epidemiological studies, there may be confounding factors that are not adequately accounted for,” says Jeffrey Lapides of Drexel University School of Medicine in Pennsylvania, but the vaccine's effect on dementia remains plausible. I agree with that. And it's worth further research.
Conclusive evidence will come from randomized controlled trials in which patients are assigned either the active drug or a placebo. Dementia progresses so slowly that it will take years to collect enough data to demonstrate that BCG and other vaccines offer promising protection against full-blown Alzheimer's compared to a placebo. takes.
Meanwhile, scientists have begun investigating specific biomarkers that indicate early stages of the disease. Until recently, this was extremely difficult to do without expensive brain scans, but new experimental methods are now allowing scientists to isolate and measure levels of amyloid beta protein in plasma, allowing subsequent diagnosis. can be predicted with reasonable accuracy.
Preliminary research by Thomas Dow, an associate professor at the University of Wisconsin-Madison, and colleagues suggests that BCG injections can effectively lower plasma amyloid levels, especially in patients with genetic mutations associated with high risk of Alzheimer's disease. ing. Although the sample size was small, with only 49 participants in total, it raised hopes that immune training could be an effective strategy to combat this disease. “These results were encouraging,” says Weinberg, who was not involved in the study.
Weinberg has his own reasons for optimism. Working with Dr. Stephen Arnold and Dr. Dennis Faustman, he collected samples of the cerebrospinal fluid that flushes around the central nervous system of vaccinated and unvaccinated people. Their aim was to see if the effects of trained immunity could reach the brain, and that's exactly what they discovered. “These specific populations of immune cells after BCG vaccination have a stronger response to the pathogen,” Weinberg says.
We hope that these early results will prompt further trials. For Weinberg, it's simple. “The BCG vaccine is safe and available worldwide,” he says. It's also incredibly cheap compared to other options, costing just a few pence per dose. Even if it provides only a small amount of protection, “it definitely wins the cost-benefit contest,” he says.
As Calmette and Guerin discovered with potato slicing more than a century ago, progress may come when you least expect it.
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