Mutation Protects Men From Alzheimer's Disease, Hints Of Treatment

The man should have developed Alzheimer's disease in his early 40s – he had a gene mutation that guaranteed it, or so it seemed. Scans of his brain even revealed severe atrophy and the hallmarks of the disease: rough, tough amyloid plaques and tau protein wrinkled like spaghetti. But the fatal brain disease didn't appear until the man was 67 years old.

Now intense research efforts have discovered why. The man was protected because another mutation in a different gene prevented the disease from entering his entorhinal cortex. That small area of ​​the brain is a hub for neurons involved in memory, object recognition, navigation and the perception of time. And it is there that scientists believe that Alzheimer's disease begins.

A paper about the findings published Monday in the journal Nature Medicine.

More than six million people in the United States suffer from Alzheimer's, a very difficult disease to treat. But here is a man with a mutation that causes the most severe and rapidly progressing form of Alzheimer's. And the disease was delayed for two decades. If a drug can do what the mutation, which causes most people to develop Alzheimer's in very old age, the results could be transformative.

“This really holds the secret for the next generation of therapies,” says Dr. Joseph F. Arboleda-Velasquez, cell biologist at Massachusetts Eye and Ear in Boston and member of the research team. Dr. Arboleda-Velasquez is a co-founder of a biotechnology company that wants to produce a drug that can be used for this research.

A drug that delays disease by two decades is not out of the question, says Dr. Diego Sepulveda-Falla, a neurologist at the University of Hamburg in Germany and a member of the research team. The mutation results in a potent version of the protein, Reelin, in the entorhinal cortex. The incredibly strong reelin ultimately prevents the tangled tau protein strands from sticking together and forming the structure that is a hallmark of Alzheimer's.

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

But such treatments will be discontinued in the future and may not be possible, said Dr. Thomas Bird, emeritus professor of neurology and clinical genetics at the University of Washington. Dr. Bird was not involved in this research.

The entorhinal cortex is a very small area. “We don't know what kind of damage there might have been, sticking needles and dropping chemicals,” he said.

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

Several years ago, the same research group in the current study identified a woman who was also protected against Alzheimer's. But in his case, the resistance was caused by mutations in a different gene, APOE. Instead of lacking tau clumps in one small area of ​​his brain, they were missing all over his brain.

But, say the researchers, they think the two patients reveal a new way to treat Alzheimer's. Two mutated genes disrupt the molecular cascade of events necessary for tau to assemble in the brain.

The hypothesis that a drug may protect the entorhinal cortex in other patients requires further research. But animal studies have been done, says Dr. Arboleda-Velasquez. Members of the group injected a mutant form of Reelin into the same brain areas in mice predisposed to diseases such as Alzheimer's to see if it was protective.

The future may involve a combination of therapies, says Dr. Eric Reiman, member of the research team, executive director of the Banner Alzheimer's Institute in Phoenix and paid adviser to several drug companies. The hope is to prevent amyloid and tau buildup and delay Alzheimer's in those who are susceptible so long that they are no longer a problem.