Mutation protects men from Alzheimer’s, suggests cure

This man was supposed to have Alzheimer’s disease in his early 40s — he had, or seemed to have, a genetic mutation that ensured it. Scans of his brain also revealed severe atrophy and the rough, hard amyloid plaques and spaghetti-like tangles of tau protein that characterize the disease. But the fatal brain disease didn’t develop until the man was 67.

Now, intensive research efforts have revealed why. This man was protected because another mutation in another gene prevented the disease from penetrating the entorhinal cortex. That small region of the brain is the hub of neurons involved in memory, object recognition, navigation and time perception. And scientists believe that’s where Alzheimer’s disease begins.

A paper on the findings was published Monday in Nature Medicine.

Alzheimer’s disease affects more than 6 million people in the United States, and the disease is notoriously difficult to treat. But here was a man with a mutation that causes the most severe and rapidly progressing Alzheimer’s disease. And his illness was delayed by 20 years. If drugs do the same thing as mutations, and most people develop Alzheimer’s later in life, the outcome could be very different.

“This really holds the secret to the next generation of treatments,” said Dr. Joseph F. Arboleda Velázquez, a cell biologist at the Massachusetts Eye Clinic in Boston and a member of the research team. Dr. Arboleda Velázquez is the co-founder of a biotechnology company aiming to produce drugs that act on this research.

Dr. Diego Sepulveda Falla, a neuropathologist at the University of Hamburg in Germany and a member of the research team, said it was not impossible to develop a drug that could delay the disease by 20 years. This mutation produces Reelin, a potent protein in the entorhinal cortex. This extremely potent Reelin ultimately prevents the tangled chains of the tau protein from sticking together to form the structures characteristic of Alzheimer’s disease.

The idea, he said, is to “use a syringe to treat just one area of ​​the brain.”

But such treatments may become obsolete and impossible in the future, warned Dr. Thomas Byrd, emeritus professor of neurology and clinical genetics at the University of Washington. Dr. Byrd was not involved in this study.

The entorhinal cortex is a very small area. “We don’t know what harm a needle stick or a chemical drop could do,” he says.

The man, whom researchers call “resilience” to Alzheimer’s disease, was part of a decades-long study of 6,000 Colombians with genetic mutations that cause Alzheimer’s disease in middle age. Many people consent to genetic testing, brain scans, and postmortem brain autopsies.

A few years ago, the same research group as the current study identified a woman who was also protected from Alzheimer’s disease. But in her case, resilience was caused by mutations in another gene, APOE. Instead of missing tau clumps in a small area of ​​her brain, her whole brain was missing tau clumps.

But researchers say they believe the two patients may reveal a new treatment for Alzheimer’s disease. Her two mutated genes disrupt a series of molecular cascades required for tau to aggregate in the brain.

The hypothesis that a drug can protect the entorhinal cortex in other patients requires further research. But animal testing is already underway, said Dr. Arboleda Velázquez. Members of the research group are injecting mutant forms of Reelin into the same brain regions of Alzheimer’s disease-prone mice to see if they have a protective effect.

Eric Lyman, Ph.D., a member of the research team, executive director of the Banner Alzheimer’s Institute in Phoenix, and a paid consultant to a number of pharmaceutical companies, said a combination of treatments may be needed in the future. said to be sexual. The hope is to prevent the accumulation of amyloid and tau, delaying Alzheimer’s disease in susceptible people for long enough that it is no longer a problem.

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