Mutation protected human from Alzheimer’s disease, suggesting treatment
The news
The man should have developed Alzheimer’s in his early forties – or so it seemed, he had a gene mutation that guaranteed it. 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 deadly brain disease did not occur until the man was 67.
Now an intense research effort has discovered why. The man was protected because another mutation in another gene prevented the disease from entering his entorhinal cortex. That small part of the brain is a hub for neurons involved in memory, object recognition, navigation and timekeeping. And it is there that scientists believe Alzheimer’s disease begins.
a paper the finding was published Monday in the journal Nature Medicine.
Why it matters: A possible path to treatment.
More than six million people in the United States have Alzheimer’s disease, a disease that is notoriously difficult to treat. But here was a man with a mutation that causes the most severe and rapidly progressing form of Alzheimer’s. And his illness was delayed for two decades. If a drug could do what the mutation did, causing most people to develop Alzheimer’s at a very late age, the result could be transformative.
“This really holds the secret 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. Dr. Arboleda-Rodriguez is co-founder of a biotechnology company that aims to produce drugs that could contribute to this research.
A drug that slows the disease by two decades is not ruled out, said Dr. Diego Sepulveda-Falla, a neuropathologist at the University of Hamburg in Germany and a member of the research team. The mutation results in a potent version of a protein, Reelin, in the entorhinal cortex. That super-powered Reelin ultimately prevents tangled strands of tau proteins from sticking together and forming the structures that characterize Alzheimer’s disease.
The idea is to “go in with a syringe and treat just one part of the brain,” he said.
But that kind of treatment is out in the future and may not be possible, Dr. Thomas Bird, professor emeritus of neurology and clinical genetics at the University of Washington. Dr. Bird was not involved in the investigation.
The entorhinal cortex is a very small area. “We don’t know what damage it can do, stick needles in it and drop chemicals in it,” he said.
Background: A new look at ongoing research.
The man with what the researchers call “resilience” to Alzheimer’s was part of a decades-long study of 6,000 people living in Colombia who have a gene mutation that causes middle-aged Alzheimer’s. Many have agreed to genetic testing, brain scans and, after death, brain autopsies.
A few years ago, the same research group in the current study identified a woman who was also protected against Alzheimer’s disease. But in her case, resilience was caused by a mutation in another gene, APOE. Instead of missing clumps of tau in a small part of her brain, they were missing in her entire brain.
But, the researchers say, they think the two patients may reveal a new way to treat Alzheimer’s disease. The two genes that are mutated interrupt a molecular cascade of events necessary for tau to aggregate in the brain.
What’s Next: Additional research and combined treatments.
The hypothesis that a drug could protect the entorhinal cortex of other patients requires more research. But animal studies are already underway, said Dr. Arboleda-Velasquez. Members of the group are injecting the mutated form of Reelin into the same part of the brain in mice prone to an Alzheimer’s-like disease to see if it is protective.
The future may involve a combination of therapies, said Dr. Eric Reiman, a member of the research team, executive director of Banner Alzheimer’s Institute in Phoenix and a paid consultant to a number of pharmaceutical companies. The hope is to prevent the buildup of amyloid and tau and delay Alzheimer’s disease long enough that it is no longer a problem.