Mutation Protected Man From Alzheimer’s Disease, Hinting at Treatment

The News

The man should have gotten 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 atrophying and the hallmarks of the disease: rough, hard, amyloid plaques and spaghetti-like tangles of tau proteins. But the fatal brain disease did not appear until the man was 67.

Now an intense research effort has discovered why. The man was protected because another mutation in a different gene blocked the disease from entering his entorhinal cortex. That tiny area of the brain is a hub for neurons involved in memory, recognition of objects, navigation and time perception. And it is there that scientists believe that Alzheimer’s disease begins.

A paper on the finding was published Monday in the journal Nature Medicine.

Why It Matters: A potential path to treatment.

More than six million people in the United States have Alzheimer’s, a disease that has been notoriously difficult to treat. Yet here was a man with a mutation that causes the most severe and rapidly progressing form of Alzheimer’s. And his disease was delayed for two decades. If a drug could do what the mutation did, resulting in most people getting Alzheimer’s very late in life, the outcome could be transformative.

“This really holds the secret to the next generation of therapeutics,” 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-Velasquez is a co-founder of a biotechnology company looking to produce drugs that could act on 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 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-potent Reelin ultimately prevents tangled strands of tau proteins from sticking together and forming the structures that are a characteristic of Alzheimer’s.

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

But that sort of treatment is off in the future and may not be possible, cautioned Dr. Thomas Bird, emeritus professor of neurology and clinical genetics at the University of Washington. Dr. Bird was not involved in the study.

The entorhinal cortex is a very small area. “We don’t know what sort of damage it might do, sticking needles in and dropping in chemicals,” he said.

Background: A new take from ongoing research.

The man with what the researchers are calling “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 Alzheimer’s in middle age. Many have agreed to genetic testing, brain scans and, after they die, brain autopsies.

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

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

What’s Next: Additional research and combined treatments.

The hypothesis that a drug could protect other patients’ entorhinal cortexes requires more research. But animal studies are already underway, Dr. Arboleda-Velasquez said. Members of the group are injecting the mutant form of Reelin into the same part of the brain in mice that are predisposed 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 adviser to a number of drug companies. The hope is to prevent the buildup of amyloid and tau and to delay Alzheimer’s in those susceptible for so long that it is no longer an issue.