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Rare Human Mutation Discovered to Shield Against Alzheimer’s Disease

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Mary McNally
Mary McNally is a UK-based author exploring the intersection of fashion, culture, and communication. With a talent for vivid storytelling, Mary's writing captures the complexities of modern life engagingly and authentically.

For many, a family history of Alzheimer’s may seem like a heavy, ominous cloud hanging in the sky.

But a faint streak of light breaks through the clouds: scientists spotted a second person who should have experienced Alzheimer’s symptoms at age 40, but didn’t.

The disease joins another identified years ago with a genetic mutation thought to have played a role in delaying the onset of signs of latent Alzheimer’s disease.

The Colombian retired at the age of 60, and only then, years later, at the age of 67, did the first signs of cognitive decline appear.

Brain scans revealed that his brain was atrophied and had the classic molecular hallmarks of the disease: large numbers of sticky protein clumps known as amyloid plaques, along with several complex tangles of another protein called tau. These types of aggregates are commonly seen in people with severe dementia. However, this man somehow battled Alzheimer’s for much longer than anyone expected.

It turned out that in addition to the genetic variant that predicted his prognosis, the man also had a rare variant in another gene that codes for a protein called reelin that appears to have protected him from developing Alzheimer’s for more than two decades.

And in a small, specific part of his brain where neurons are involved in memory and movement, the man had very low levels of synaptic tau. And it was as if the genetic lottery had rewarded him with a protective protein that prevents Alzheimer’s in this critical area of ​​the brain that is usually attacked very early by the disease.

While little is currently known about the role of Reelin in the development of Alzheimer’s disease, animal experiments by a team of researchers led by Colombian neurologist Francisco Lopera showed that the mutated form of Reelin also prevented tau proteins from tangling together around neurons in the brains of mice. The team’s findings are published in the journal Nature Medicine.

“It’s just an important new avenue for finding new treatments for Alzheimer’s,” neuroscientist Katherine Kazorowski, a researcher at the University of Michigan at Ann Arbor, who was not involved in the study, told Nature.

It is hoped that by studying how reelin interacts with Alzheimer’s proteins and protects neurons in their circuits, researchers may be able to find a way to increase resistance in all forms of Alzheimer’s, not just those who inherit the protective variant.

As journalist Jenny Erin Smith wrote in Undark in 2019, Alzheimer’s research “relies heavily on families with early genetic forms of the disease to understand its progression and test therapies that can disrupt it.”

In the latest study, Lopera of the University of Antioquia in Medellin, Colombia, and colleagues analyzed clinical and genetic data from nearly 1,200 members of this Colombian population. And they identified a new and very rare alternative in a man who remained cognitively intact, as well as in his sister, who was less protective than her brother and died many years ago.

And in 2019, Lopera and colleagues reported another case of a woman carrying the Paisa mutation who showed no signs of cognitive decline until age 70—about 30 years later than would be expected from carriers of the mutation. Research showed that she also had unusually low levels of tau throughout her brain, but her resistance to Alzheimer’s was attributed to a different mutation in a different gene: APOE.

The researchers believe there may be some overlap or interaction between the reelin variant and APOE, which may explain its protective effect, but it is possible that other genetic variants may also be involved. For now, Lopera and his colleagues say their results only help formulate new hypotheses about Alzheimer’s disease.

The researchers concluded that if, over time, therapies that take advantage of the reelin signaling pathway can be developed, they could have “a profound therapeutic effect on tau resistance and neurodegeneration, as well as resistance to cognitive decline and dementia in Alzheimer’s disease.”

Source: Science Alert

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