A man's rare gene variant may have shielded him from devastating form of early Alzheimer's

illustration shows a close up of a DNA molecule depicted in greyish blue
A man carried a genetic mutation that set him up to develop early-onset Alzheimer's disease, but another gene kept him healthy for many years. (Image credit: byakkaya via Getty Images)

A newly discovered genetic variant protects against a particularly devastating form of early Alzheimer's disease, raising scientists' hopes of finding treatments that can prevent or slow the progression of this and other forms of the disease. 

The discovery is only the second gene variant reported to protect against autosomal dominant Alzheimer's disease (ADAD), a form of Alzheimer's caused by an inherited genetic mutation. People with ADAD begin to show signs of dementia in their mid-40s and rarely survive past the age of 60, study co-author Dr. Joseph Arboleda-Velasquez, a biomedical researcher at Harvard University, told Live Science. 

The patient at the heart of the new study was a male member of a Colombian family that researchers have been following for a long time because they're known carriers of the genetic mutation that causes ADAD. This man carried that gene, but instead of succumbing to early dementia, he remained healthy into his late sixties and developed only mild Alzheimer's disease by age 72. He died at 73 years old of non-dementia-related causes. 

"It was just really remarkable that he made it that far, despite the odds," Arboleda-Velasquez said. 

Related: New Alzheimer's drug slightly slows cognitive decline. Experts say it's not a silver bullet.

To find out how, Arboleda-Velasquez and his colleagues sequenced the man's genes and came up with a list of genetic variants, or specific versions of genes, that might have been protective. One gene, RELN, popped out as intriguing because the protein it codes for binds to the same cellular receptors as the protein made by a well-known gene called APOE. One variant of the APOE gene raises the risk of Alzheimer's by partially driving the formation of amyloid plaques, clusters of misfolded proteins considered to be a hallmark of Alzheimer's. 

The researchers studied the effects of the RELN gene in cells in lab dishes and in mice and discovered that the variant the man carried actually made the protein that RELN codes for bind more tightly to its receptor. This effect seems to help the RELN protein stabilize the protein tau, which can form tangles in the brain that serve as another tell-tale sign of Alzheimer's.

The patient had reduced tau tangles in many parts of his brain compared to other Alzheimer's patients, but some portions still showed tau pathology. Delving deeper into the gene variant and how it protects against early-onset Alzheimer's is the crucial next step, said Dr. Kenneth Kosik, a neurologist at UC Santa Barbara who studies ADAD but who was not involved in the current research. 

The RELN variant the man carried seemed to have a different effect from the previous protective variant that this same group of researchers reported in another individual in 2019. In that first case, a woman with ADAD did not develop any signs of dementia until her 70s. Although the woman's brain had signs of amyloid plaques, no part of the organ carried high levels of misfolded tau. Instead of a RELN variant, she had an APOE variant to thank for the reduction in malformed tau, the scientists reported.  

Although the two ADAD-resistant individuals had different genetic mechanisms acting in their brains, the ultimate outcome was the same, Arboleda-Velasquez said: Reduced tau pathology and a shocking resilience to Alzheimer's. 

Neurologically, the case of the first woman was easier to unravel than this new case, Kosik told Live Science. APOE is a well-understood gene in the Alzheimer's research community, Kosik said, while RELN's functions are less well-understood.  

"If we understood the mechanism, [how] this gene controls that protein…maybe we can find a drug that would activate that pathway," he said. 

Arboleda-Velasquez and his colleagues have identified other individuals who seem to be healthy despite carrying the mutation for early-onset Alzheimer's, so they intend to continue hunting for genetic variations that confer protection. Though ADAD is only one form of Alzheimer's, it shares the same plaques, tangles, and progression as later-onset disease — only earlier and faster. Thus, researchers are optimistic that a treatment for early-onset Alzheimer's will also protect people who get the disease later in life.

"I think these cases are setting the stage for the next generation of therapies for Alzheimer's," he said.

Stephanie Pappas
Live Science Contributor

Stephanie Pappas is a contributing writer for Live Science, covering topics ranging from geoscience to archaeology to the human brain and behavior. She was previously a senior writer for Live Science but is now a freelancer based in Denver, Colorado, and regularly contributes to Scientific American and The Monitor, the monthly magazine of the American Psychological Association. Stephanie received a bachelor's degree in psychology from the University of South Carolina and a graduate certificate in science communication from the University of California, Santa Cruz.