The Spanish Society of Neurology (SEN) estimates that 80% of Alzheimer’s cases that are in the initial stages are undiagnosed. The figure is scary because only in Spain the number of diagnoses of this disease already goes for 800,000 and the aging of the population is rampant. There is no effective treatment for this terrible disease, but we do not even have an even more basic tool: an early detection that, at least, could help alleviate or slow down the deterioration.
For years, Spanish researchers have been behind a clue that seems increasingly important not only to detect the disease, but also to understand it: it is a protein present in human saliva called lactoferrin. The lower the levels, the greater the risk of a person suffering from Alzheimer’s. Therefore, it can behave as a biomarker with many advantages, since it would be very easy to take a sample and perform this evaluation.
This result already came to light in 2017 in the scientific journal ‘Alzheimer’s & Dementia’ in a publication by scientists from the Alava company Geroa Diagnostics and the Hospital 12 de Octubre in Madrid, integrated into the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED). Even then, lactoferrin levels allowed distinguish individuals who had mild cognitive impairment, Alzheimer’s patients, and healthy people. The idea of developing a test to measure protein began to gain momentum.
Since then, new research has confirmed that this finding may be key to advancing in the fight against the disease, since it is “the only protein with the potential to help diagnosis in saliva worldwide,” Gorka Orive explains to Teknautas , Associate Professor of Pharmacy at the University of the Basque Country and founder of Geroa Diagnostics. One of the most important jobs appeared in 2020 in the magazine ‘EbioMedicine’ (from ‘The Lancet’ group), signed by this expert together with the prestigious cardiologist Valentín Fuster. This article relates the drop in the level of lactoferrin in saliva with increased beta amyloid substance, the main component of senile plaques that Alzheimer’s patients present. The research was carried out with neuroimaging techniques in people with different neurodegenerative disorders.
Now, a new study is revealing. Scientists from the Pablo de Olavide University of Seville and Ciberned, led by the researcher José Luis Cantero, have verified in an experiment with 74 people over 65 years of age that the protein in saliva is not only related to beta amyloid levels, but also with very mild memory impairments. This work is important because it is about “cognitively healthy individuals, but that damage accumulates in the brain, in the form of beta amyloid or atrophies in the cerebral cortex ”, explains Orive, who has not participated directly in this research. The result not only confirms the connection between the biomarker and Alzheimer’s, but also suggests that this decrease in lactoferrin could be detected even before the symptoms with which the disease is usually diagnosed appear.
This would confirm that the biomarker can become an early test for Alzheimer’s, although Orive is cautious about it so as not to generate unfounded expectations. “This work confirms that there is a progressive fall in lactoferrin as the situation worsens, but I would not dare to draw the scenario of a marker prior to the symptoms. until we can validate it faithfully. In the meantime, we are going to try to learn as much as possible ”, he says.
The ideal would be to analyze the data in a longitudinal study, that is, to include thousands of participants aged 45 years and over and monitor them for decades. As this involves many resources and above all too much time, what the researchers do are cohort studies, so that they do not have that film in time, but they do have a photograph of groups of patients that share characteristics to be able to make comparisons. Thus, the investigations include Alzheimer’s patients, patients with cognitive impairment (a stage prior to the disease) and healthy people of different ages. At the moment, all the studies are confirming that low levels of lactoferrin are related to a greater risk, while people who have high levels of this protein are free of symptoms.
In search of explanations
But why does this protein disappear as Alzheimer’s progresses? Researchers are also looking for an answer to this question, not only to confirm that it is a reliable marker, but because it would likely be key to understanding the origin of the disease. Lactoferrin is a component of the immune response innate. Among other functions, “it is an antioxidant, anti-inflammatory substance and an iron transporter”, explains the expert. In addition, “it plays an important role in terms of the oral cavity to contain pathogens” and this may be decisive in explaining how its levels are related to the development of Alzheimer’s. The mouth is a route of entry for many infections and diseases in general, so some researchers hypothesize that the entry of pathogens by mouth could lead to chronic infections and even access the central nervous system.
In fact, some Alzheimer’s patients have found oral pathogens in the brain. An investigation published in ‘Science Advances’ in 2019 showed that the gingivitis bacteria, which causes inflammation of the gums, produce a protein that can reach the brain and destroy neurons. Although more research is needed, this theory makes a lot of sense because it has already been proven that dental diseases can trigger other health problems, for example, cardiovascular ones (the mechanism would be the same: the entry of pathogens through the oral route).
Thus, the alteration in lactoferrin levels could be due to some pathogen. However, there are other explanations as well. “There are molecular mechanisms by which the hippocampus can control the secretion of some proteins of the immune response ”, comments the professor at the University of the Basque Country. Whatever the answer, “we try to analyze how that brain that is getting sick in some way modifies the levels of this protein in the salivary glands.”
The business challenge
In any case, Geroa Diagnostics has patented it as a biomarker for the diagnosis of Alzheimer’s and hopes that the opportunity will open to market a product in test form. “We have intellectual and industrial protection and we are collaborating with important companies in the diagnostics sector, so we hope that in the coming months we can take important steps”, explains Orive. The prospects are very good because as a marker it is easy to measure, simple and inexpensive; But the path to such an innovation is always complex. The Basque startup has to think about the business strategy and the regulatory part. Meanwhile, “science must never stop, we must continue studying and validating the marker outside our borders, with international cohorts, that is very important,” says the researcher.
Dr. Ángel Durántez
In fact, this branch of research seems to be in turmoil. “Saliva is a fluid that has not been studied enough, but that it has many potentialities and that it can begin to have a lot of relevance in analysis and diagnoses ”, he affirms. The pandemic has proven it. In a few months, we went from diagnosing covid with PCR to other faster and cheaper tests and among them there was no lack of detection of positives through saliva tests. At the same time, something seems to be moving in Alzheimer’s research after decades of stagnation. The US Food and Drug Administration (FDA) recently approved the drug aducanumab, although it has generated much controversy and doubts among experts. Alzheimer’s remains a huge challenge, but the aging society is asking for solutions.