Mutation protected man from Alzheimer’s disease – 05/16/2023 – Health

The man must have contracted Alzheimer’s disease in his 40s — he had a genetic mutation that guaranteed it, or so it seemed. Scans of his brain even revealed severe atrophy and the hallmarks of the disease: rough, hard amyloid plaques and spaghetti-like tangles of tau proteins. But the fatal brain disease didn’t appear until the man was 67 years old.

Now, an intense research effort has uncovered why. The man was protected because another mutation in a different gene blocked the disease from entering his entorhinal cortex. This small area of ​​the brain is a hub for neurons involved in memory, object recognition, navigation, and time perception. And this is where scientists believe Alzheimer’s disease begins.

An article about the discovery was published on Monday (15) in the journal Nature Medicine.

More than 6 million people in the United States have Alzheimer’s, a notoriously difficult disease to treat. However, that man had a mutation that causes the most severe and rapidly progressing form of the disease. And it was delayed for two decades. If a drug could do what the mutation did, causing most people to get Alzheimer’s well later in life, the result could be transformative.

“This really holds the key to the next generation of therapies,” said Dr. Joseph F. Arboleda-Velasquez, a cell biologist at Massachusetts Eye and Ear in Boston and a member of the research team.

Arboleda-Velasquez is the co-founder of a biotechnology company that seeks to produce drugs capable of acting in this research.

A drug that delays the disease by two decades is not out of the question, said Dr. Diego Sepulveda-Falla, a neuropathologist at the University of Hamburg, Germany, and a member of the research team. The mutation results in a potent version of a protein, reelin, in the entorhinal cortex. This super-potent reelin prevents tangled strands of tau proteins from coming together and forming the structures that are a hallmark of Alzheimer’s disease.

The idea is to “go in with a syringe and treat just one area” of the brain, he said.

But that kind of treatment is far in the future and may not be possible, warned Dr. Thomas Bird, professor emeritus of neurology and clinical genetics at the University of Washington. Bird did not participate in the study.

The entorhinal cortex is a very small area.

“We don’t know what kind of damage we could do by sticking needles and throwing chemicals,” he said.

The man with what researchers call Alzheimer’s “resilience” participated in a decades-long study of 6,000 people living in Colombia who have a genetic mutation that causes Alzheimer’s in middle age. Many agreed to genetic testing, brain scans and, after they died, brain autopsies.

A few years ago, the same research group as the current study identified a woman who was also protected against Alzheimer’s disease. But in her case, the resilience was caused by a mutation in a different gene, APOE. Instead of missing tau clusters in a small region of his brain, they were missing across the entire brain.

But, say the researchers, they think the two patients are revealing a new way to treat Alzheimer’s disease. The two mutated genes interrupt a molecular cascade of events necessary for tau to aggregate in the brain.

The hypothesis that a drug could protect the entorhinal cortex of other patients requires further research. But animal studies are already underway, Arboleda-Velasquez said. Members of the group are injecting the mutated form of reelin into the same part of the brain of mice predisposed to an Alzheimer’s-like disease to see if it provides protection.

The future may involve a combination of therapies, said Dr. Eric Reiman, a member of the research team, executive director of the Banner Alzheimer’s Institute in Phoenix and a paid consultant to several pharmaceutical companies. The hope is to prevent amyloid and tau buildup and delay Alzheimer’s disease in susceptible people for so long that it is no longer a problem.

^{Translated by Luiz Roberto M. Gonçalves}