A healthy brain includes tens of billions of neurons that process and transmit information to the muscles and organs of the body. When Alzheimer's disease develops, that communication between neurons is disrupted. It can lead to loss of function and death of those cells. The results of the largest genetic study on Alzheimer's disease in the world have now become known. He provided convincing evidence linking the disease to alterations of the brain's immune system.
The study was led by scientists from Europe. The genomes of 100,000 people with Alzheimer's and 600,000 healthy people were used. They were able to identify 75 genes associated with an increased risk of suffering from the disease, including 42 that had not been previously implicated.
The researchers who conducted the study, which was published in the journal Nature Genetics, are part of scientific institutions and universities in France, Belgium, Holland, Spain, United Kingdom, Germany, United States, Finland, Sweden, Norway, Australia, Greece, Italy, Bulgaria, Iceland, Denmark, Portugal, Austria, Cyprus, Czech Republic, and Switzerland. Researchers from Argentina and Brazil participated from Latin America.
One of the co-authors is Dr. Laura Morelli, from the Instituto Leloir Foundation and the Conicet of Argentina. When interviewed by Infobae, Morelli said that the research consisted of processing information on “a large number of cases and controls in the European population and more precisely defined the genetic profile associated with the risk of suffering from Alzheimer's disease”.
What is the benefit of that achievement? “With the genetic information associated with the risk of Alzheimer's, it was possible to establish the metabolic pathways linked to the neurodegenerative process characteristic of Alzheimer's disease. In this way, possible new therapeutic targets for treatment can be identified,” Morelli said.
“Once we have the data of the gene that is associated with the risk of the disease, what is done is to see what protein is encoded by that gene. That protein is then placed in a biological pathway. For example, if the protein is associated with an inflammatory process, then it can be suggested that inflammation is linked to the disease and speculate that patients can be treated with anti-inflammatory drugs,” added Dr. Morelli.
The scientist Morelli, together with Ignacio Brusco, from the Department of Physiological Sciences of the Faculty of Medicine of the University of Buenos Aires and the Eva Perón Hospital in San Martín, Carolina Muchnik, from the Lanari Institute of the UBA, and the group of Silvia Kochen, from the Hospital El Cruce, the Arturo Jauretche University and the Conicet, were some of the co-authors of the study.
“Our group, together with other research groups in Argentina, is part of a consortium dedicated to the recruitment and genetic analysis of cases and controls of ancestry mixed between Europeans and Amerindians. This population is useful to the European consortium that led the work to validate its findings in a population of different ethnic origin. The work at Nature Genetics did not include patients from Argentina,” Morelli said.
The results of research published in Nature Genetics suggest that degeneration in the brains of dementia patients may be stimulated by the “excessively aggressive” activity of the brain's immune cells, called microglia.
Professor Julie Williams, director of the UK Institute for Dementia Research at Cardiff University and co-author of the study, told The Guardian newspaper that the findings could help revive efforts to find effective treatment. “This is a huge clue as to what is going wrong,” he said. “Eight or nine years ago we didn't work on the immune system. Genetics has reoriented us.”
The study also allowed scientists to devise a genetic risk score that could predict which patients with cognitive impairment would develop Alzheimer's within three years of the onset of the first symptoms. The score is not intended for clinical use at this time, but could be used when recruiting people for clinical trials of drugs intended to treat the disease in its earliest stages.
Today there are also more than 55 million people living with dementias around the world, and it has already been predicted that this type of mental disorder will affect 139 million by 2050. Alzheimer's disease is the most common cause of dementia. Despite the enormous burden of the disease, there have been no new drugs in the last two decades, with the exception of Aducanumab, which is controversially authorized in the United States.
Previous research has shown that while lifestyle factors such as smoking, exercise and diet influence the risk of Alzheimer's, between 60% and 80% of the risk of the disease is genetic-based. However, according to Williams, drug development has been greatly influenced by the study of families with rare genetic mutations that cause the early onset of Alzheimer's.
Among the risk genes highlighted in the study are those that affect the effectiveness of immune cells in the brain, microglia, to eliminate tissue that is in danger. In people at risk, these cleaning cells seemed to work too aggressively.
“I am quite optimistic about the existence of treatments that work for some of the systems we are studying,” Williams said. The findings fit with previous results that point to a role of the immune system. People with diabetes, which affects the immune system, have a considerably higher risk, for example, and once dementia is diagnosed, infections can trigger cognitive decline faster.
Dr. Susan Kohlhaas, director of research at Alzheimer's Research in the UK, said of the published study: “Creating a comprehensive list of Alzheimer's disease risk genes is like having the pieces of a puzzle together, and while this work does not give us the complete picture, it provides a valuable framework for future developments. However, research also tells us how complex Alzheimer's is, with several different mechanisms involved in the development of the disease.”
When asked by Infobae, Pablo Richly, director of the Center for Brain Health (CESAL) and member of the Association of Argentine Psychiatrists, said: “The work provides more evidence on the correlation between genes and Alzheimer's disease. This type of results is always welcome to generate new hypotheses and lines of research.” But the doctor, who was not involved in the work, clarified: “However, we are still far from being able to predict what impact this could have in the future in the office.”
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