Man With Rare Genetic Mutation Experiences 20-Year Delay in Alzheimer’s Symptoms Despite Having Molecular Hallmarks of the Disease [Study]

A man who was supposed to experience symptoms of Alzheimer's disease in his early 40s was saved due to a genetic mutation. The man still experienced the symptoms of the disease, but not until 20 years later, when he was already in his 60s.

Alzheimer's Disease Symptoms Delayed Due to Genetic Mutation

Years ago, a genetic mutation was suspected to have contributed to the delay of a man's underlying Alzheimer's pathology. The Colombian man didn't get a life-changing diagnosis in his prime; instead, he continued working until he retired in his early 60s, and it wasn't until he was 67 that the first signs of cognitive deterioration were apparent, ScienceAlert reported.

His brain had atrophied and was filled with the typical molecular signs of the disease, such as numerous sticky protein clumps called amyloid plaques and a small number of tangled knots of another protein called tau. People with severe dementia frequently exhibit these aggregates. However, the man has so far managed to fend off Alzheimer's for two decades, longer than what was expected.

They later discovered that man also had an uncommon variant in his gene that codes for a protein called reelin, which seems to have prevented him from getting Alzheimer's for over two decades. The genetic mutation seemingly protected him from the symptoms of the brain disorder that slowly destroys one's memory, thinking skills, and ability to carry out simple tasks, per NIH.

The man had very low levels of twisted tau in a limited, focused area of his brain where neurons important in memory and navigation reside. In this one crucial area of the brain that typically succumbs to the disease relatively early, it was as if the genetic lottery had bestowed upon him a protective protein that kept Alzheimer's disease at bay.

Although there is currently little information regarding reelin's function in Alzheimer's disease, animal studies conducted by a research team led by Colombian neurologist Francisco Lopera noted that the mutated form of reelin inhibited the tau protein from knotting together around the neurons of the mice's brain.

The study was published in Nature Medicine.

Reelin Study For Alzheimer's Disease

Researchers hope to learn more about how reelin interacts with Alzheimer's proteins and defends neurons from their clutches to find a strategy to increase resilience in people with all types of Alzheimer's disease, not only those who inherit its protective variation.

The researchers are still learning much about Alzheimer's disease from families like the one Lopera has been observing in Colombia for almost 40 years. Many of the man's extended family, which spans decades and generations, and some 6,000 individuals, carry a mutation that makes Alzheimer's first manifest in middle life.

It is frequently referred to as the Paisa mutation in honor of those in Colombia's Antioquia area who have donated their bodies, brains, and blood to advance scientific understanding.

Lopera, from the University of Antioquia in Medellin, Colombia, and colleagues examined clinical and genetic information from nearly 1,200 members of that Colombian kindred for the most recent study. The man who retained cognitive function and his sister, who had less protection than her brother and had passed several years before, both had the brand-new, incredibly unusual mutation they could identify.

In 2019, Lopera and his coworkers published another instance of a lady with the Paisa mutation who didn't begin to experience cognitive deterioration until she was in her 70s, around 30 years later than what is typical for gene carriers. Studies revealed that she also had remarkably low tau levels all over her brain, but her resistance to Alzheimer's was related to a distinct mutation in the APOE gene.

According to Science Board, Paisa mutation carriers usually develop mild cognitive impairment at 44 and dementia at 49, then die from dementia complications in their 60s. However, the male in Lopera's study remained cognitively intact until he was 67.

Neuroscientist Catherine Kaczorowski, who was not involved in the study, told Nature she had goosebumps while reading the report. According to Kaczorowski, a researcher at the University of Michigan in Ann Arbor, it offers a significant path in pursuing new treatments for Alzheimer's disease.

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