2023-05-21 08:39:11
When a Colombian man was first examined by neurologists at the age of 67, he was found to be cognitively normal. He and his family were not at all concerned about his memory, but scientists began to closely monitor his unusual case. The patient – a mechanic, husband to wife and father of two – was born with a genetic mutation that was supposed to give him dementia before his fiftieth birthday. But instead, his life was one of remarkable resilience, in stark contrast to the script written by his genes. The cognitive impairment that should have erupted at the age of 44 remained dormant for more than two decades. Instead of dying in his early sixties, he retired. In the end, he did develop moderate dementia, and died in 2019 at the age of 74.
This man is only the second patient known to doctors who had the remarkable ability to develop resistance against the devastating Alzheimer’s gene, an international team of scientists reported this week in the journal Nature Medicine. Doctors hope that these two special cases will allow researchers to develop new treatments to protect other people with Alzheimer’s disease, which affects 6.7 million people in the US alone.
The researchers closely studied the patient’s genome to identify another mutation that may have helped protect him from the disease. They also used brain scans taken when he was 73 to focus on a key region that appeared to be relatively protected from the tau protein tangles that commonly occur in Alzheimer’s patients. “It is important that we listen to the patients. And what the patients are telling us is that there is a path to protection,” says Joseph P. Arboleda-Vlasquez, an associate scientist at Harvard Hospital and one of the leaders of the study.
“These are very provocative findings, and I think these cases have something very important to teach us about disease resistance and the biology of Alzheimer’s,” says Gil Rabinovici, a neurologist at the University of California, San Francisco, who was not involved in the research. “I think the research raises interesting questions. I don’t know if we have answers.”
A genetic time bomb
For decades, neuroscientist Francisco Lopera of the University of Antioquia in Medellin, Colombia, has been treating and following an extended family, many of whose members carry a devastating mutation called presenilin 1. The mutation is rare, and its effects are aggressive and predictable: in their late twenties, the brains of people who carry the mutation become clogged with the characteristic amyloid plaque Alzheimer’s disease. In their mid-thirties, tangles of another protein associated with Alzheimer’s, tau, appear. People who carry this gene begin to experience the first signs of cognitive problems around the age of 44, and by the age of 49 they already develop full dementia. They usually die in their sixties.
In all, scientists discovered, in an extended family of more than 6,000 people, 1,200 people carrying this genetic time bomb. Yakil T. Quiroz, director of the Familial Dementia Imaging Laboratory at Massachusetts General Hospital, has worked with Lopra and these patients for twenty years. “You meet them before they have symptoms, and you see them progress,” Quiroz says. “You can stick around and watch how they develop severe dementia – and how they die. You can’t do anything to stop it.”
But in 2019, researchers discovered a single patient, Elyria Rosa Federhita de Villegas, who seemed to have postponed the end. Her memory didn’t begin to deteriorate until she was in her seventies. Scientists discovered a genetic mutation that protected her, and named her “Christchurch”. Although her brain was full of the amyloids characteristic of Alzheimer’s, it was relatively free of the tau tangles also associated with the disease.
Scientists marveled at the case but also debated its relevance. It was just one person. Was this an aberration, or a path to healing worth exploring? What can one person tell us about how to fight Alzheimer’s in the wider population? Therefore, the discovery of a second person with genetic resilience validates the effort – but also deepens the mystery. In the body of the Colombian, who remained anonymous at the request of his family, there was no Christchurch mutation. It seems that he was protected due to a mutation in another gene, named Rilin. Moreover, the brains of both patients were loaded with the amyloid plaques, which have until now been a major target in Alzheimer’s treatments.
Recently, drugs aimed at clearing amyloids have been approved in the US – the first signs of hope in decades. But these drugs are far from being distributed to the public. They aim to slow the progression of the disease, but have also sparked debate and criticism as to whether the modest benefits outweigh the risks and are worth the costs.
The absence of tau tangles in the first patient supported an alternative avenue for treatment. When the Colombian traveled to Massachusetts to undergo a brain scan at the age of 73, researchers discovered both the amyloids and the tau tangles associated with Alzheimer’s disease. But significantly, the tau was relatively limited in its entorhinal cortex, which is essential for memory. “By protecting the entorhinal cortex, even if there is a lot of Alzheimer’s pathology elsewhere, is it possible to produce such protection? It would be amazing. It’s very tempting,” says Arbolda-Vlasquez.
Scientists, including those involved in the research, caution that it is far from providing an explanation for why the patient’s memory was protected for years. There could be several contributing factors, rather than one explanation. But the possibility that a person can have a high level of protection against deterioration, even if their brain is substantially affected by amyloid and tau accumulation, is “intriguing,” according to Inmaculada Cochillo-Ibáñez, a researcher at the Institute of Neuroscience at Miguel Hernández University in Alicante, Spain.
She studied the protein hirlin in the brains of people with more common forms of Alzheimer’s disease: “This suggests that this gene could turn out to be critical in protecting against cognitive impairment.”
The researchers did find an overlap between the two different genetic mutations that helped protect these people: both mutations affect proteins that bind to the same receptors in brain cells. The scientists also found that mice genetically predisposed to develop tau tangles in their brains were less likely to do so when they carried the mutation in the hrilin gene found in the Columbian.
Understanding the possible biochemical pathways that created protection opens up new approaches to drug development, the researchers say. According to Kuroz, the man’s family members were excited that something useful had been learned from his case. Both patients and researchers are aware that the disease is moving so fast that discoveries may only benefit future generations. But according to Lopera, these exceptional cases point to the way forward: “Both cases have a huge potential to benefit all Alzheimer’s patients or those who are at risk of getting it, because they show a way to prevention and cure.”
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