For many years, there was a stigmatized village in Antioquia, in northwestern Colombia. In Yarumal, embedded in the mountains with some 35,000 inhabitants, an important group of people began to lose memory, mobility and finally autonomy after turning 40. The generality thought that the people of this village were cursed.
What happened to them was that they developed the degenerative disease of Alzheimer’s disease at a very early age –premature Alzheimer’s.
Francisco Lopera, a neurologist, and Lucía Madrigal, a psychologist and nurse, reversed the stigma with scientific research, not only in Yarumal, but also in other villages in Antioquia: Ituango, Angostura and Belmira. It all began in 1984, when Lopera did his residency in neurology and treated a 47-year-old woman who had lost her memory. He went on digging and found that the same thing had happened to his patient’s father, grandparents and uncles, as Catalina Oquendo writes in a report in El País.
The scientific work grew over time and so did the team, who now work in the Antioquia Neuroscience Group (GNA in Spanish). To date they have studied 6,000 people from 25 families. They found that in all of the 1,200 people who had developed the disease the gene presenilina 1 was present, which made them manifest Alzheimer’s decades before the common type of the disease.
They were also related. The early Alzheimer’s of these people was, then, hereditary.
This genetic mutation would later be called the “Paisa mutation.”
The complicated access to these towns due to the orography of this area of Antioquia made Yarumal a “genetic island”, as Oquendo quotes one of the scientists of the GNA, David Aguillón. The village inhabitants, mostly peasants, married among themselves, although of the 6,000 people studied by neuroscientists, they found that only 1,200 were carriers of the paisa mutation.
After 35 years of study, the case of a 73-year-old woman arrived at the Antioquia Neuroscience Group. She has the “Paisa mutation” but she did not develop Alzheimer’s until after she was 70. A gene carrier resisted the disease into old age. This opens for these scientifics a new line of research and possible new treatments for hereditary Alzheimer’s.
The cause of Alzheimer’s is yet unknown, although it affects 50 million people worldwide and is the leading cause of dementia on the planet, according to the World Health Organization. Each year there are 10 million new cases, so the WHO estimates that within 30 years, in 2050, those affected in the world will have tripled.
Alzheimer’s begins to occur when the brain is bathed in “junk proteins”, as Lopera calls them, the beta-almyloid proteins, which destroy neurons. However, the symptoms take up to 20 years to develop with a new marker: one type of these proteins, the tau, prevents neurons from communicating with each other and thus impairs memory, as journalist Nuño Domínguez writes in another report for El País. The brain of this 73-year-old patient who did not develop early Alzheimer’s was full of betas almiloides but had very few tau.
The researchers published the study on her this November in the journal Nature Medicine.
Researcher Kenneth Kosik, of the Santa Barbara Campus at the University of California a, joined Lopera and Madrigal a few years ago. He began a clinical trial in 2013, writes Dominguez in the report, with 300 patients. Some have the paisa mutation and others do not. The purpose is to demonstrate whether a drug called crenezunam is capable of preventing the appearance of Alzheimer’s disease. “It is a study almost impossible to carry out anywhere else in the world, because here doctors know who will develop Alzheimer’s almost certainly,” writes Domínguez. The results of these studies will be ready in 2022.
It was in this trial that they found the 73-year-old patient who had resisted the disease.
They determined that in her brain was the APOE gene, which makes Alzheimer’s the most likely to occur, but in a very rare variant, APOE 3 Chrischurch, and in two copies.
Dominguez reports that another Colombian, Yakeel Quiroz, who is a researcher at the Massachusetts General Hospital in Boston, developed an antibody that mimics the “mutation effect” of this patient, who still carries the genetic mutation but has barely lost her memory at her age. “What we have seen is that the protein generated by this patient’s APOE gene interferes with the union of APOE and HSPG proteins, which promotes the accumulation of amyloid proteins and also tau,” Domínguez quotes Quiroz findings. That could have make possible, the researchers infer, that this woman’s neurons continued to function 30 years after the age at which, due to the Paisa mutation, she should have developed the disease. This is, then a new mutation, a protective one, according to the scientists.
The development of this antibody could reproduce the same in other brains. If so, scientists would test whether it works as the first treatment for hereditary Alzheimer’s disease.
“If we could imitate the same in the general population we would delay the onset of the disease by three decades,” Quiroz tells Domínguez, although he warns that there is still much scientific work to be done for this to apply to those who suffer from Alzheimer’s disease today. For the time being, they will continue to study the family of this 73-year-old woman to see if they have a mutation like her that protects them from developing early Alzheimer’s disease.
It also remains for them to locate the first family that suffered the genetic Paisa mutation caused by Alzheimer’s at the age of 40. Catalina Oquendo points out in her report that Francisco Lopera and Lucía Madrigal studied the ancestors of Yarumal’s families until 1740, but Kenneth Kosik told Nacho Domínguez that he thinks the mutation could have come to America from Spain during the Conquest. The journalist writes that Konik’s team is working with Spanish scientists to find Spanish families who also have hereditary Alzheimer’s, perhaps because of the same gene as the patients in Yarumal.