A man with a rare mutation that protects him from Alzheimer’s disease: ScienceAlert

For many, a family history of Alzheimer’s disease would seem like a heavy, ominous cloud hanging over their heads. But through the clouds comes a faint burst of light: Scientists have discovered a second person who should have been experiencing symptoms of Alzheimer’s in their early 40s, but didn’t.

The case joins another who was identified several years ago with a genetic mutation thought to have played a role in delaying signs of his own underlying Alzheimer’s disease.

Instead of receiving a life-changing diagnosis in his prime, the recently described Colombian man continued to work until he retired in his early 60s, and only then, years later, at age 67, the first signs of cognitive decline materialized.

Brain scans revealed that his brain had atrophied and was laden with the classic molecular hallmarks of the disease: an elevated number of clumps of sticky proteins called amyloid plaques, along with some knotted tangles of another protein called tau. These types of aggregates are usually seen in people with severe dementia. Yet the man had somehow resisted Alzheimer’s disease much longer than expected.

It turns out that in addition to the genetic variant that predicted his diagnosis, the man also carried a rare variant of another gene coding for a protein called reelin that apparently protected him against developing Alzheimer’s disease for more than two decades.

In a specific small part of his brain where neurons are involved in memory and navigation, the man had very low levels of entangled tau. It was as if the genetic lottery had gifted him with a protective protein that kept Alzheimer’s disease at bay in that critical region of the brain that usually succumbs to the disease quite early.

Although little is known about the role of reelin in 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 tying themselves around neurons in mouse brains. The team’s findings are published natural medicine.

Neuroscientist Catherine Kaczorowski, who was not involved in the research, said Nature that reading the newspaper “made my hair stand on end”.

“It’s just such an important new avenue for pursuing new therapies for Alzheimer’s disease,” said Kaczorowski, a researcher at the University of Michigan at Ann Arbor.

The hope is that by studying how reelin interacts with Alzheimer’s proteins and protects neurons in their clutches, researchers could potentially find a way to build resilience in all forms of Alzheimer’s disease, and not only in those who inherit its protective variant.

Yet it is from families like the one that Lopera has followed in Colombia for nearly 40 years that we learn so much about Alzheimer’s disease. In the man’s extended family, which spans decades, generations and some 6,000 people, many harbor a common mutation that causes Alzheimer’s to strike early, in middle age.

It is usually called the Paisa mutation after those from the Antioquia region of Colombia, who volunteered their blood, body and brain to help the research.

As journalist Jennie Erin Smith wrote for Undark in 2019, Alzheimer’s disease research “relies heavily on families with early genetic forms of the disease to understand its progress and test therapies that may interrupt”.

In the latest study, Lopera, from the University of Antioquia in Medellín, Colombia, and her colleagues analyzed clinical and genetic data from approximately 1,200 individuals from this Colombian family. They identified the extremely rare new variant in humans who remained cognitively intact, as well as his sister, who was less protected than her brother and died years earlier.

In 2019, Lopera and colleagues reported another case of a female carrier of the Paisa mutation who showed no signs of cognitive decline until her 70s – about 30 years later than expected for carriers of the Paisa mutation. mutation. Studies have shown that she, too, has abnormally low levels of tau throughout her brain, but her resistance to Alzheimer’s disease has been attributed to a different mutation in another gene: APOE.

The researchers believe that there may be an overlap or interaction between the reeline variant and the APOE proteins that could explain their protective effect, but it is possible that other genetic variants also contribute. For now, Lopera and his colleagues say their findings only help to formulate new hypotheses about Alzheimer’s disease.

Over time, if treatments to tap into the reelin signaling pathway could be developed, they “could have a profound therapeutic impact on resistance to tau pathology and neurodegeneration, and resilience against cognitive decline and dementia in Alzheimer’s disease”, conclude the researchers.

The research has been published in Natural medicine.

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