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Rare Mutation That Provides Alzheimer’s Protection Identified

A rare mutation in a man offers hope for Alzheimer’s treatment as a permanent.

Alzheimer, Mutation, Genes
A cure for Alzheimer's has always proved elusive to scientists. Could this new discovery hold the key to unlocking a new era of treatment? Credit: LightField Studios / Shutterstock

To many folks out there, having a family history of Alzheimer‘s disease can be as heavy as a dark cloud looming overhead, casting a foreboding shadow over their lives.

But hey, amidst those gloomy clouds, a glimmer of hope emerges: scientists have stumbled upon a second individual who should have been plagued by Alzheimer’s symptoms in their early forties and yet, defied all odds and sailed through unscathed.

This new case joins the ranks of another remarkable person identified a few years back. This extraordinary individual possessed a genetic mutation that seemed to have played a part in delaying the onset of Alzheimer’s pathology. Instead of receiving a life-altering diagnosis in their prime, this Colombian hero continued working tirelessly until their early sixties. Years later, at the spry age of sixty-seven, the first whispers of cognitive decline emerged.

Brain scans laid bare the truth—a truth both perplexing and astonishing. The man’s brain had withered and become a breeding ground for the classic molecular markers of the disease: heaps of sticky protein clumps known as amyloid plaques and a scattering of knotted tangles of tau protein. These mischievous aggregates are typically associated with folks suffering from severe dementia. Yet, this man had somehow managed to hold off the relentless onslaught of Alzheimer’s for far longer than anyone could fathom.

As it turns out, alongside the genetic variant that foretold his fate, this remarkable individual carried a rare variant in another gene, which encoded a protein aptly named reelin. This seemingly magical protein acted as a guardian, shielding him from succumbing to Alzheimer’s disease for over two decades.

Within a tiny, specialized nook of his brain, where neurons dance to the tune of memory and navigation, the man possessed staggeringly low levels of tangled tau. It was as if the genetic lottery had bestowed upon him a protective talisman, a protein knight that valiantly battled Alzheimer’s within this critical brain region, an area prone to early capitulation in the face of the disease.

While the role of reelin in Alzheimer’s disease remains a bit of a mystery, a team of intrepid researchers, led by the Colombian neurologist Francisco Lopera, conducted animal experiments that shed some light on the subject. They discovered that the mutated form of reelin also prevented the entangling of tau proteins around neurons in the brains of mice. Their groundbreaking findings have been published in Nature Medicine.

Neuroscientist Catherine Kaczorowski, who had no hand in this research, admitted that reading their paper sent shivers down her spine. “It’s just such an important new avenue to pursue new therapies for Alzheimer’s disease,” exclaimed Kaczorowski, a researcher hailing from the University of Michigan in Ann Arbor.

The grand hope now rests upon unraveling the intricate dance between reelin and the Alzheimer’s proteins, understanding how they interact, and ultimately discovering a way to fortify resilience against all forms of the disease. The quest for a cure expands beyond the realm of those fortunate enough to inherit this protective variant.

But let’s not forget the families that have served as the backbone of our knowledge about Alzheimer’s disease. For nearly four decades, Lopera has closely followed a remarkable lineage in Colombia. This extended family, spanning generations and encompassing a staggering 6,000 individuals, harbors a common mutation that causes Alzheimer’s to strike in the prime of life, during middle age.

This mutation is often referred to as the Paisa mutation, a tribute to the resilient souls in Colombia’s Antioquia region who have generously offered their blood, bodies, and brains to propel our research forward.

As journalist Jennie Erin Smith eloquently noted in her piece for Undark in 2019, the study of Alzheimer’s disease

heavily relies on families affected by the early-onset, genetic forms of the condition. Their experiences illuminate the path towards understanding the disease’s progression and testing potential therapies that might intervene in its relentless march.

In this latest study, Lopera, stationed at the University of Antioquia in Medellín, Colombia, joined forces with colleagues to meticulously analyze clinical and genetic data from around 1,200 individuals within the Colombian kinship. Within this treasure trove of information, they unearthed the new and exceptionally rare variant present in the man who remained mentally sharp, as well as his sister, who, despite being less protected, valiantly fought the disease until her untimely demise.

Back in 2019, Lopera and his comrades revealed another captivating case—an individual carrying the Paisa mutation who only displayed cognitive decline in her seventies, a good thirty years later than expected for carriers of the mutation. Research unveiled unusually low levels of tau throughout her brain, but her resilience to Alzheimer’s was attributed to a different mutation in another gene, APOE.

Scientists suspect that there might be some intricate interplay or overlap between the variant reelin and APOE proteins that could account for their protective effects. Of course, it’s entirely possible that other genetic variants may contribute to this enigma. For now, Lopera and his colleagues cautiously state that their findings merely serve as the building blocks for new hypotheses about Alzheimer’s disease.

Given time, and if we manage to develop treatments that tap into the reelin signaling pathway, we may unleash a profound therapeutic impact on the resilience against tau pathology and neurodegeneration. Perhaps then, we can shield ourselves from the ravages of cognitive decline and dementia in Alzheimer’s disease.

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