A Man’s Rare Genetic Mutation May Have Prevented Alzheimer’s for Decades

For decades, scientists have studied the members of an extended family in Colombia, who tend to have a genetic mutation that leads to early-onset Alzheimer’s. Several people in that family develop symptoms of the progressive, memory-destroying disease as early as their 40s.

But in a new study in the journal Nature Medicine, scientists share the case of a man in this family who, despite having the same mutation, did not show signs of cognitive decline until the age of 67.

The researchers found he also had a rare, different mutation that may have helped stave off the onset of Alzheimer’s. The finding could help develop treatments for the disease.

“Reading that paper made the hair on my arms stand up,” Catherine Kaczorowski, a neuroscientist at the University of Michigan who did not contribute to the research, tells Nature News’ Sara Reardon. “It’s just such an important new avenue to pursue new therapies for Alzheimer’s disease.”

The new study is the research team’s second paper to identify a variant that may help prevent cognitive issues in a member of the Colombian family. But some researchers caution that more work is needed.

“The results look very promising, but it would be useful to see replication in more samples,” Rudolph Tanzi, a neurologist at Harvard Medical School who was not involved in the work, tells Science News’ Simon Makin. But the research “can serve as a useful guide for drug discovery.”

Alzheimer’s disease causes a decline in memory and cognition. More than an estimated 6 million Americans over the age of 65 have the disease, according to the National Institute on Aging. Researchers are still trying to better understand what causes Alzheimer’s, but studies point to proteins called beta-amyloid and tau, which build up around and within brain cells, respectively.

In 40 years of research, experts have studied 6,000 people in the Colombian family and identified 1,200 with the mutation that causes early symptoms of Alzheimer’s, per Nature News. A Spanish conquistador may have first introduced the mutation to the area during colonization in the 17th century, according to New Scientist’s Clare Wilson.

People with the mutation start developing mild cognitive impairment at the median age of 44 and dementia at 49. They often die in their 60s, writes the Washington Post’s Carolyn Y. Johnson.

But at the age of 67, when the man in the new study was evaluated for the first time, he only had minor cognitive issues, per Nature News. He was diagnosed with mild cognitive impairment at 70, with a decline in his short-term memory and verbal fluency, the study authors write. At 72, he was diagnosed with mild dementia, and he died from pneumonia at 74.

The man’s sister carried the same mutation, and though she experienced dementia earlier than he did, it still came 12 years later than expected for members of her family, per the paper. In the earlier study, researchers describe a woman with a different mutation who did not show signs of cognitive decline until almost 30 years later than expected.

Both the man and the woman from the earlier study had high levels of plaques between their brain cells from buildups of beta-amyloid proteins, per the Washington Post. But they had fewer tangles of tau proteins within their brain cells—the woman had lower levels of tau tangles throughout her brain, and the man had low levels of tau buildup in certain brain regions including the entorhinal cortex—an area that plays a role in memory and is thought to be where Alzheimer’s originates.

The findings suggest that Alzheimer’s is more complicated than thought, and that there could be multiple types of the disease, some of which aren’t caused by amyloid plaques, Yadong Huang, a neurologist at the Gladstone Institute who wasn’t involved in the study, tells Nature News. These two cases point to tau being largely responsible for Alzheimer’s symptoms.

“Tau is more important [than amyloid],” Diego Sepulveda-Falla, a co-author of the study and a neurologist at the University Medical Center Hamburg-Eppendorf in Germany, tells New Scientist. “I think we have enough evidence to say it.”

Researchers are now searching for treatments based on these findings, per the New York Times’ Gina Kolata. But whether the mutation described in the study is what’s protecting people from Alzheimer’s is still an open question—the authors also identified additional variants that may have played a role in delaying the man’s cognitive decline.

“It’s very difficult to be sure which variant, or variants, endowed our brains with that resilience,” Nikolas Robakis, who researches Alzheimer’s at the Icahn School of Medicine at Mount Sinai and did not contribute to the research, tells Stat News’ Andrew Joseph. “We’ll have to do lots of work on that.”

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Will Sullivan is a science writer based in Washington, D.C. His work has appeared in Inside Science and NOVA Next.