27 MAY 2023
To many, a family history of Alzheimer’s disease would feel like a heavy, ominous cloud hanging overhead. But through the clouds comes a faint shard of light: scientists have discovered a second person who should have experienced symptoms of Alzheimer’s in his 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 her own underlying Alzheimer’s pathology.
Instead of receiving a life-altering diagnosis in his prime, the recently described Colombian man carried on working until he retired in his early 60s, and only then, years later at 67, did the first signs of cognitive decline materialize.
Brain scans revealed his brain had atrophied and was laden with the classic, molecular hallmarks of the disease: high numbers of sticky protein clumps known as amyloid plaques, along with a few knotted tangles of another protein called tau. These kinds of aggregates are usually seen in people with severe dementia. Yet the man had somehow resisted Alzheimer’s disease far longer than anyone expected.
It turns out, that in addition to the genetic variant that foretold his diagnosis, the man also carried a rare variant in another gene encoding a protein called reelin that seemingly protected him from developing Alzheimer’s disease for more than two decades.
In one small, specific part of his brain where neurons are involved in memory and navigation, the man had very low levels of tangled tau. It was as if the genetic lottery had gifted him a protective protein that held Alzheimer’s disease at bay in this one critical brain region that usually succumbs to the disease quite early.
While little is currently known about reelin’s role in Alzheimer’s disease, animal experiments by a team of researchers headed up by Colombian neurologist Francisco Lopera showed that the mutated form of reelin also stopped tau proteins knotting together around neurons in the brains of mice. The team’s findings are published Nature Medicine.
Neuroscientist Catherine Kaczorowski, who was not involved in the research, told Nature that reading the paper “made the hair on my arms stand up.”
“It’s just such an important new avenue to pursue new therapies for Alzheimer’s disease,” said Kaczorowski, a researcher at the University of Michigan in 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 boost resilience across all forms of Alzheimer’s disease, and not just in those who inherit its protective variant.
Though it is from families like the one Lopera has been following in Colombia for nearly 40 years that we are learning 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 typically referred to as the Paisa mutation after those in Colombia’s Antioquia region, who have offered up their blood, bodies, and brains to aid research.
As journalist Jennie Erin Smith wrote for Undark in 2019, Alzheimer’s research “leans heavily on families with early-onset, genetic forms of the disease to understand its progress and test therapies that might interrupt it.”
In the latest study, Lopera, at the University of Antioquia in Medellín, Colombia, and colleagues analyzed clinical and genetic data from about 1,200 individuals of that Colombian kindred. They identified the new and extremely rare variant in the man who remained cognitively intact, as well as his sister, who was less protected than her brother and died years earlier.
In 2019, Lopera and his colleagues reported another case of a woman carrying the Paisa mutation who showed no signs of cognitive decline until her 70s – some 30-odd years later than expected for carriers of the mutation. Studies showed she too had unusually low levels of tau throughout her brain, but her resilience to Alzheimer’s was attributed to a different mutation in another gene: APOE.
Researchers think there may be some overlap or interplay between the variant reelin and APOE proteins that could explain their protective effect, yet it’s possible that other genetic variants contribute too. For now, Lopera and colleagues say their findings only help shape new hypotheses about Alzheimer’s disease.
In time, if treatments to tap into the reelin signaling pathway could be developed, they “may have a profound therapeutic impact on the resistance to tau pathology and neurodegeneration, and resilience against cognitive decline and dementia in Alzheimer’s disease,” the researchers conclude.