They discover the second case in the world of a man 'immune' to Alzheimer's

Four years ago, a group of researchers found a woman, Aliria Rosa Piedrahita, who could hold the key to the most common dementia in the world, Alzheimer's.. That genetic footprint is now added to another that they have found in a 67-year-old man and that will serve as a new clue to the neurological disease that affects more than 38 million people worldwide..

On this occasion, the piece of the puzzle that man carries is in the RELN gene, H3447R (called Reelin-Colbos by the Colombia-Boston biomarker research study), which encodes the reelin signaling protein, key in the main alterations Cognitive and biochemical characteristics of tau protein-related dementias. In the case of women, the mystery lies in a rare mutation in the APOE3 gene, one of those responsible for the development of neurodegeneration, which acts as a brake against the appearance of symptoms associated with Alzheimer's disease.. “We have characterized the second case in the world in which we have verified resilience against autosomal dominant Alzheimer's disease (ADAD),” the authors explain in Nature Medicine..

The research team that found the man and the new mutation is the same one that found the woman. The multidisciplinary group of the Medical School of the Harvard University, the University Medical Center of Hamburg-Eppendorf and the Neurosciences Group of the Faculty of Medicine, of the University of Antioquia in Medellín (Colombia) have been solving puzzles of mutations for decades. genes that cause Alzheimer's among related inhabitants of the rural region of Antioquia and that cause the appearance of symptoms at very early ages.

To put both cases in context, Joseph F.. Arboleda-Velasquez, one of the authors and an associate professor at Harvard Medical School, explains to EL MUNDO that “if in the protected woman the mutation was in the APOE gene, now in the male the mutation is in the Reelin gene.”. And he goes on to provide details of the differences in each case.. “In her, the APOE mutation was named Christchurch, the tests showed a brain that had many amyloid plaques, but little accumulation of tau, another protein that is also important in Alzheimer's.. In man, a high presence of both proteins, both amyloid and tau, has also been observed, which indicates that it is possible to be protected even when the clinical pathology of Alzheimer's is high”.

ADAD is a rare inherited form of dementia and is commonly caused by specific mutations in the PSEN1-E280A gene encoding the transmembrane protein presenilin 1.. “It is characterized by the early onset of cognitive decline, such as memory deficits, at an early age, typically 40-50 years of age,” the researchers explain..

The publication puts into context the situation of the man compared to that of his sister who did develop the clinical symptoms of Alzheimer's and ended up dying at the age of 73, with a host of associated pathologies, after starting dementia at the age of 61.. Both shared the PSEN1-E280A mutation with the Reelin variant. She also had a delayed age of onset of cognitive decline, albeit with less protection compared to her brother and prolonged end-stage disease.. “The sister had a history of a severe head injury, which required reconstructive surgery, as well as a history of depression and hypothyroidism.. These factors may have had an impact on their clinical profile and should be taken into account when evaluating their phenotype,” the authors point out in the conclusions..

The researchers explain that they compared the male with the female, both with late ADAD.. “Both people showed widespread and considerable amyloid pathology in the brain, which is a pathological hallmark of Alzheimer's disease.”. And they point out the differences found: “However, there was limited aggregation of tau (a microtubule stabilizing protein in the brain) in the entorhinal cortex, a region of the brain that is characteristically affected in the early clinical stages of Alzheimer's disease.” “.

To verify what was going on, the authors performed genetic sequencing and found that the male harbored a different type of mutation: a new rare variant of RELN (H3447R called Reelin-COLBOS).. The researchers detail the complex processes that serve to explain developmental resistance to manifestations of neurodegeneration that “this mutation results in a RELN ligand, a binding molecule, which may be more effective in limiting tau aggregation, but for what more research is needed”. The APOE and Reelin proteins involved in the protection of these individuals function as ligands for common cellular receptors, and the authors note that this could suggest a common mechanism for Alzheimer's resistance..

How would you know if you have these Alzheimer's genes?

With these discoveries, it is possible to speculate if there will be more people who meet these traits and if there would be a possibility of proposing a screening to find them.. “While it is really easy to carry out genetic studies to look for the variant, however, we are dealing with a very rare mutation. Therefore, it is most likely that it will be found in few patients,” laments Arboleda-Velasquez.

Despite this, the Harvard researcher underlines the participation of the studied community. “It is important to recognize the contribution of patients who with much sacrifice participate in clinical and genetic studies. They are the heroes of this discovery”.

In 2019, the woman's case came to light in Nature Medicine after research on 1,200 Colombian individuals with a specific mutation in the presenilin protein 1 (PSEN1) gene.. These people are predisposed to developing this disorder, ADAD, and almost always experience cognitive problems and dementia at an unusually young age..

In both cases, time was waited to verify that the individuals did not develop the manifestations of neurodegeneration.. “The genetic variant was identified several years ago in this patient, but it took time to carry out genetic and molecular studies to confirm its role in the protection process,” says Arboleda-Velasquez..

Yakeel Quiroz, also responsible for the study on genetic mutation. HARVARD UNIVERSITY

In Colombia, the Antioquia Neurosciences Group attached to the Faculty of Medicine of the University of Antioquia, has already identified 11 genetic variants in PSEN1; of which, the genetic variant PSEN1-E280A is present in about 6,000 people distributed in 25 families, originating in different municipalities of Antioquia, for this reason, it is known as the “paisa mutation”. This is the largest population group in the world with hereditary Alzheimer's disease.

Aliria Rosa Piedrahíta died at the age of 77 from melanoma and donated her brain to continue the study of her 'shield' against Alzheimer's. He remained until he was 72 years old without signs of the disease, after they discovered that he should have developed neurodegeneration around the age of 44 and died at the age of 60.. His case is being studied in the laboratory of the Antioquia Neuroscience Group.

A door to new therapies against Alzheimer's

Although there has been good news in the treatment of Alzheimer's in recent times, the characterization of these new genetic clues may offer short-term options.. “Each of these patients opens the door to various therapies. We are advancing in the antibody inspired by the Christchurch case and we also have progress in the approaches inspired by the Reelin case”, details Arboleda-Velasquez.

Currently, Lecanemab is already available in the US for patients. It is a monoclonal antibody developed by the Japanese company Eisai and the American Biogen indicated for patients who are in the earliest stages of the disease. The drug has managed to reduce the rate of early cognitive decline by 27% compared to a placebo.