This vaccine you got as a child can actually fight Alzheimer's disease?

More than 100 years ago, Calmette and Gering's discovery on potato chips helped humans defeat a terrible disease that once took lives wantonly; more than 100 years later, will the unexpected connection between BCG and Alzheimer's disease win another battle? Is it true or false? Science will eventually give the answer.

Compiled by Xiaoye

BCG, a vaccine that almost everyone in China knows and every newborn must be vaccinated with, is becoming a new favorite of scientists. They want to use it to conquer another century-old disease, Alzheimer's disease, and have made a number of advances in recent years.

New understanding of amyloid

Anyone who knows about Alzheimer's disease must be familiar with the "amyloid hypothesis." Although the hypothesis has been controversial in recent years, it is still the mainstream theory to explain the pathogenesis of Alzheimer's disease, and researchers have also used it as a target to study various treatments. The theory assumes that the gradual accumulation of β-amyloid protein in the brain triggers a complex cascade reaction: neuronal cell death, neuronal synapse loss, and progressive neurotransmitter deficiency. All of these effects ultimately lead to the clinical symptoms of dementia. [1]

So, if we go back further, what exactly causes the formation of amyloid-β plaques? There is still no answer.

In 2022, a paper published in PLoS Pathogens[2] proposed a new pathogenic pathway, namely pathogen infection-immune system operation-β-amyloid accumulation-neurodegenerative disease. Specifically, when we are young, our own defense system can resist bacteria, viruses or fungi from entering the brain. However, as we age, the ability of immune cells declines, and microorganisms take the opportunity to enter the neural tissue. The immune system produces β-amyloid to kill invading microorganisms and play a short-term protective role. If the brain's immune cells, namely microglia, can work properly, they can clear these amyloid proteins after the pathogen crisis is resolved. However, in many cases of Alzheimer's patients, microglia seem to have dysfunction and cannot be cleaned up in time, so amyloid proteins continue to deposit and plaque, which in turn begins to damage neurons. In fact, related autopsy reports published in the 1990s[3] found that common microorganisms, such as the herpes simplex virus type 1 that causes cold sores, parasitize the brains of Alzheimer's patients. These microorganisms are usually trapped in amyloid.

Figure 1: The picture shows that after pathogens infect the central nervous system, the immune response is activated, and the accumulation of β-amyloid protein is one of the means to eliminate the pathogen, but amyloid protein deposition plaques will also form later. Source:
10.1371/journal.ppat.1010929

In fact, there are studies in the academic community that have reported another unknown property of β-amyloid protein: resistance to microorganisms. A review article published in the Journal of Alzheimer's Disease in 2018 [4] provides a lot of research evidence showing that in humans and animal models, brain infection further stimulates the processing of β-amyloid precursor protein, including the production of proteins composed of 40- and 42-amino acid residues after degradation and cleavage. These two proteins are also the main forms of β-amyloid protein in the brains of Alzheimer's patients. They are prone to fibrosis and aggregation to form soluble aggregates of different sizes. β-amyloid protein oligomers are one of them [5]. Scientists have shown through in vivo and in vitro experiments that these oligomers have strong broad-spectrum antimicrobial properties, can capture pathogens, destroy their cell walls, and continuously resist bacterial and viral infections. Clinical trials for Alzheimer's disease that clear β-amyloid protein have observed an increase in the degree of subsequent infection in patients.

In the same year, another study [6] revealed that β-amyloid oligomers can bind to herpes virus surface glycoproteins through mouse models and human neuronal cell culture infection models, accelerating β-amyloid deposition on the one hand and capturing neurotropic herpes simplex virus 1 (HSV1) and human herpes virus 6A and B on the other hand. This once again supports the claim that β-amyloid may play a protective role in the innate immune process of the central nervous system.

This shows that the short-term activity of β-amyloid protein helps the brain eliminate invading microorganisms, but then it turns from a "right-hand man" to a possible "disease killer" due to immune dysfunction. In fact, targeting β-amyloid protein has been one of the strategies used by the academic community to design drugs for Alzheimer's disease for many years. After decades of research, the US Food and Drug Administration has only approved two monoclonal antibody drugs for the treatment of early Alzheimer's disease: ADUHELM[7] and Leqembi[8]. They can selectively bind to β-amyloid protein deposits in the patient's brain, neutralize and eliminate them, and alleviate the disease progression of some patients, but the improvement in overall quality of life is often limited, and there are certain adverse reactions[9].

The new understanding of the characteristics of β-amyloid protein provides another way to combat it: if the overall function of the immune system can be enhanced instead of just eliminating β-amyloid protein deposits, perhaps immune cells can clear the deposited plaques in a timely manner and prevent further lesions from occurring.

Centennial medicine shows new uses

Sometimes scientific discoveries occur in the most unexpected places.

Back in the early 20th century in France, doctor Albert Calmette and veterinarian Camille Guérin worked together to find a way to spread bovine tuberculosis. To do this, they first needed to culture the bacteria, and they found that cooking sliced ​​potatoes with cow bile and glycerin made a perfect culture medium for the bacteria. But as they grew, they were surprised to find that with each generation of bacteria, they became less virulent, and each generation became less virulent. Then, even after multiple generations of cultured bacteria, animals no longer got sick and were no longer infected by wild tuberculosis bacteria. In 1921, the doctors tested the vaccine on their first human patient, a baby whose mother had just died of tuberculosis, and it worked. Thus, the Calmette-Guérin vaccine, also known as the BCG vaccine, was born and widely used, saving millions of lives.

The two doctors who invented BCG, Albert Calmette on the left and Camille Guérin on the right, a veterinarian

However, Calmet and Gering could never have imagined that their research would inspire scientists more than a century later to use BCG to study a completely different disease and come to an unexpected conclusion: BCG might protect people's brains from developing Alzheimer's disease.

This statement may sound outrageous, but academic research over the past few decades has shown that the protection provided by BCG is unexpectedly broad, far beyond its original purpose. For example, a meta-analysis study published in the journal Vaccines[10] revealed that BCG can reduce the risk of respiratory tract infections. Another double-blind randomized clinical trial[11] showed that BCG vaccination can provide strong protection against the risk of respiratory tract infections.

In addition to respiratory infections, BCG is also used as a standard treatment for non-muscle invasive bladder cancer: the delivery of attenuated bacteria to the organ activates the immune system to eliminate tumors, thereby reducing the risk of tumor recurrence and the possibility of cancer progressing to a more aggressive form of the disease. [12]

Even during the COVID-19 pandemic, some studies have suggested that BCG may have a protective effect against COVID-19 infection. For example, researchers from Virginia Tech, the National Institute of Allergy and Infectious Diseases, and other institutions in the United States published a report in the Proceedings of the National Academy of Sciences (PNAS) in July 2020[13], in which they reviewed the potential biological evidence for BCG to prevent COVID-19 infection. After excluding potential interference factors, they found that in European countries with similar national conditions, there was a significant correlation between a country's BCG vaccination rate and the COVID-19 mortality rate. For every 10% increase in BCG vaccination rate, the COVID-19 mortality rate would decrease by 10.4%.

Specifically, animal model studies have provided some preliminary evidence for the use of BCG in the treatment of Alzheimer’s disease. In 2017, a team from the Zhongshan Medical College of Sun Yat-sen University in China published a paper[14] that found that, through experiments on Alzheimer’s disease mouse models, the recruitment of monocytes that play a role in reducing inflammation in the brains of mice vaccinated with BCG was enhanced and gathered in the plaque lesion areas in the brain; at the same time, more circulating interferon-γ, which can enhance immune function, was produced, and the levels of anti-inflammatory cytokines were upregulated, ultimately alleviating brain inflammation in the model mice.

The reason why BCG can play an immune-enhancing role in the above studies is due to the process of "immune system training". When individuals are vaccinated with BCG, the expression of genes related to cytokine production changes. Cytokines are small molecules that can activate other defense mechanisms in our body, including white blood cells, so that the body can more effectively respond to threats, including foreign invading viruses or bacteria, or uncontrollable cell mutations.

In this way, BCG's "immune system training" is linked to the idea of ​​preventing Alzheimer's disease by strengthening the immune system as mentioned above: through training, the body's defense capabilities are enhanced, blocking pathogens before they enter the brain. In addition, the enhanced immune system can also promptly and effectively remove beta-amyloid proteins from the brain without harming healthy neural tissue.

Good news continues, but caution is needed

Since BCG vaccination has produced positive effects in mouse model experiments, does it also work for humans? To answer this question, multiple research teams around the world have begun exploring.

Source: pixabay

Ofer Gofrit's team at Hadassah Hebrew University Medical Center in Jerusalem collected data on 1,371 bladder cancer patients with an average age of 68.1 years who had or had not received BCG treatment. During the follow-up period, it was found that patients who had received BCG treatment had a risk of developing Alzheimer's disease that was more than four times lower than those who had not received BCG treatment [15]. The results were published in the journal PLOS ONE in 2019, and other research teams have since successfully replicated the results.

In 2023, Marc S. Weinberg's team from Massachusetts General Hospital in Boston published the results of a cohort study in JAMA Network Open [16]. They surveyed approximately 6,500 elderly patients with non-muscle invasive bladder cancer in Massachusetts and found that BCG treatment was associated with a lower risk of Alzheimer's disease and related dementias.

However, different studies have shown different degrees of BCG reduction in the risk of Alzheimer's disease. A meta-analysis in August 2023 also looked at the effect of BCG treatment on the risk of dementia in bladder cancer patients [17]. It searched six major relevant data sets until May 20, 2023, evaluated 4043 records, and finally analyzed 5 research papers involving 45,407 patients. The results showed that there was a significant correlation between BCG and the incidence of dementia in bladder cancer patients, and that BCG treatment could reduce the incidence of dementia by an average of 45%.

The figure of 45% is surprising and gratifying. However, this is only a meta-study and further research is needed to confirm it. If this is indeed the case, it will have a huge impact on the prevention of Alzheimer's disease. Professor Charles Greenblatt of the Hebrew University of Jerusalem commented: "Delaying the development of Alzheimer's disease by just a few years will greatly reduce people's suffering and save a lot of money." [18]

Despite the good news, it is important to remain cautious. First, existing papers have reported mostly on patients with bladder cancer, and there is little data on the general population. An obvious research strategy is to compare people who received BCG in childhood with those who did not, but this has a major drawback: the effect of BCG may become negligible over the decades, long before most people are at risk of developing Alzheimer's.

Secondly, none of these studies have provided proof of causality, only proof of correlation. "In epidemiological studies, there may be all kinds of confounding factors lurking, and researchers may not have fully considered these potential factors," said Jeffrey Lapides of Drexel University College of Medicine in Pennsylvania. Although he agrees that the impact of BCG on dementia is reasonable, more research is needed to prove it. Definitive evidence requires randomized controlled trials to assign patients to receive treatment or take a placebo. However, the development of dementia is a rather slow and long process, and it may take years or even longer to collect more data to prove that BCG or other vaccines can provide ideal protection against Alzheimer's disease.

Coad Thomas Dow's team at the University of Wisconsin-Madison conducted a pilot study and published the results in the journal Microorganisms in 2022 [19]. The team recruited 49 subjects and found that BCG vaccination can effectively reduce plasma amyloid protein levels, especially in subjects carrying genes associated with a higher risk of Alzheimer's disease. In addition, younger subjects, subjects with higher risk levels, subjects who were not latently infected with cytomegalovirus, and subjects with good lymphocyte immune risk conditions all showed statistically significant favorable changes. Although the sample size of this study is small, it has strengthened the confidence to continue to explore the strategy of preventing Alzheimer's disease through immune training.

Inspired by the new research on BCG, some scientists have also set their sights on other vaccines. Although BCG is considered to provide the most effective immune training because it contains attenuated live bacteria, other vaccines also stimulate the body's immune system, such as the flu vaccine. A cohort analysis study[20] showed that after controlling for confounding factors, participants who had received the flu vaccine and were 75.5 years old on average were significantly less likely to develop dementia than those who had not received the flu vaccine.

Nicola Veronese's team at the University of Palermo (UNIPA) in Italy analyzed the conclusions of nine studies [21], many of which controlled for lifestyle factors including income, education, smoking, drinking and high blood pressure. The results showed that influenza vaccination was associated with a 29% reduced risk of dementia, and there was also a correlation between vaccination dose and dementia incidence.

Medical experts who are committed to preventing Alzheimer's disease through vaccines are optimistic. Weinberg is active at the forefront of research. He collaborated with Dr. Steven Arnold and Dr. Denise Faustman to collect samples of cerebrospinal fluid surrounding the central nervous system of vaccinated and unvaccinated subjects. Their goal is to check whether the immune training effect triggered by the vaccine can reach the brain. "After BCG vaccination, these immune cells responded more strongly to pathogens," Weinberg said.

According to statistics released by the World Health Organization in 2023, there are currently more than 55 million people suffering from dementia worldwide, of which Alzheimer’s disease is the most common form, accounting for 60% to 70% of the patients. [22] If vaccines can play a role in treating Alzheimer’s disease, it would be a great benefit.

More than 100 years ago, Calmette and Gering's discovery on potato chips allowed mankind to defeat a terrible disease that once took lives with impunity; more than 100 years later, whether the unexpected connection between BCG and Alzheimer's disease will win another battle, reality or illusion, science will eventually give the answer.

References

[1] https://www.msdmanuals.cn/professional/neurologic-disorders/delirium-and-dementia/alzheimer-disease

[2] https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010929

[3] https://onlinelibrary.wiley.com/doi/10.1002/jmv.1890330403

[4] https://content.iospress.com/articles/journal-of-alzheimers-disease/jad171133

[5] https://www.alzcn.com/CN/10.3969/j.issn.2096-5516.2023.01.001

[6] https://www.sciencedirect.com/science/article/pii/S0896627318305269

[7] https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-aduhelm

[8] https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval

[9] https://www.nejm.org/doi/full/10.1056/NEJMoa2212948

[10] https://www.mdpi.com/2076-393X/11/1/121

[11] https://www.cell.com/cell/fulltext/S0092-8674(20)31139-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420311399%3Fshowall%3Dtrue

[12] https://www.mdpi.com/2072-6694/14/13/3073

[13] https://www.pnas.org/doi/full/10.1073/pnas.2008410117

[14] https://www.sciencedirect.com/science/article/abs/pii/S096999611730030X?via%3Dihub

[15] https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224433

[16] https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805030

[17] https://www.frontiersin.org/articles/10.3389/fnagi.2023.1243588/full

[18] https://www.theguardian.com/society/2024/feb/25/is-the-100-year-old-tb-vaccine-a-new-secret-weapon-against-alzheimers-dementia-bcg

[19] https://www.mdpi.com/2076-2607/10/2/424

[20] https://www.sciencedirect.com/science/article/abs/pii/S0264410X21010793

[21] https://www.sciencedirect.com/science/article/abs/pii/S1568163721002816

[22] https://www.who.int/zh/news-room/fact-sheets/detail/dementia

[23] https://www.theguardian.com/society/2024/feb/25/is-the-100-year-old-tb-vaccine-a-new-secret-weapon-against-alzheimers-dementia-bcg

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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