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November 7, 2019

This woman's genetics left her at great risk for Alzheimer's—so why didn't she develop it?

Daily Briefing

    A Colombian woman's family history and genetic profile indicated she'd have Alzheimer's by the time she was 50, but researchers say an extremely rare genetic mutation staved off cognitive decline until her 70s, opening up the possibility for a new approach to Alzheimer's disease treatment, Pam Belluck reports for the New York Times

    New case studies: Keep Alzheimer's patients safe at home and in the community

    A mutation protects from Alzheimer's

    The woman, whose name researchers withheld, comes from an extended family in Colombia of roughly 6,000 people who have had dementia for centuries.

    For decades, Francisco Lopera, a Colombian neurologist at the University of Antioquia, has been collecting the family's birth and death records. In addition, Lopera has received the family's permission to study some of their deceased relatives' brains.

    Through his research, Lopera and a team of U.S. scientists discovered that the family's proclivity for Alzheimer's stemmed from a mutation on the Presenilin 1 gene. This form of hereditary early onset dementia makes up just a small portion of the roughly 30 million cases of Alzheimer's worldwide, Belluck reports, but unlike other forms of Alzheimer's, the Colombian version has been tied to a specific cause and appears in a consistent pattern.

    When the researchers learned of the woman who at age 70, had yet to develop Alzheimer's, they flew her to Boston and performed a series of brain scans and tests.

    Yakeel Quiroz, a neurologist who is the director of the familial dementia neuroimaging lab at Massachusetts General Hospital and a senior author of the study, said the woman's brain scans were confusing because her brain had large amounts of amyloid protein, a hallmark of Alzheimer's disease.

    "The highest levels of amyloid that we have seen so far," Quiroz said, adding that her amyloid protein levels were likely so high because she had lived longer than other family members with the disease.

    However, the woman exhibited few other signs of the disease. For instance, she lacked the protein called tau, which forms in the brains of Alzheimer's patients, Belluck reports, and she showed very little neurodegeneration or brain atrophy, Belluck reports.

    "Her brain was functioning really well," Quiroz said. "Compared to people who are 45 or 50, she's actually better."

    Quiroz consulted her husband and colleague, Joseph Arboleda-Velasquez, an assistant professor at Harvard Medical School and a cell biologist at Massachusetts Eye and Ear. Arboleda-Velasquez conducted a series of genetic tests and sequencing and determined the woman had an extremely rare mutation called Christchurch on the gene APOE3.

    This genetic mutation had also been present in some of the woman's family members who ultimately developed Alzheimer's early in life. But what makes the woman's mutation unique is she had two of them.

    "The fact that she had two copies, not just one, really kind of sealed the deal," Arboleda-Velasquez said.

    The woman's Christchurch mutation is located in a part of the gene that binds with a sugar-protein compound involved in spreading tau, Belluck reports. Researchers determined that the less an APOE variant binds to that compound, the less it's linked to Alzheimer's.

    That discovery "was the piece that completed the puzzle because, 'Oh, this is how the mutation has such a strong effect,'" Arboleda-Velasquez said.

    What this means for Alzheimer's research

    Guojun Bu, chair of the neuroscience department at the Mayo Clinic in Florida, who studies APOE but was not involved in the Colombian woman's case, said while the findings involved just a single case and require more research, the implications of the study could be significant.

    That's in part because clinical trials of drugs attacking the amyloid or tau have been largely unsuccessful, Bu said, and the new findings could offer researchers a new path forward.

    Yadong Huang, a senior investigator at Gladstone Institutes, who was not involved in the research, said he was "very excited to see this new study come out—the impact is dramatic."

    In a commentary on the study, Huang, who is affiliated with two companies focusing on potential APOE-related treatments, said the study challenges a leading theory on the role of amyloid proteins in Alzheimer's disease.

    Since the woman in the study had large amounts of amyloid protein but not many other indicators of Alzheimer's, "it actually illustrates, to my knowledge for the first time, a very clear dissociation of amyloid accumulation from tau pathology, neurodegeneration, and even cognitive decline," Huang wrote.

    In a study published Monday in Nature Medicine, the researchers on the Colombian case said they were able to develop a compound that could mimic the action of the mutation, suggesting it could be possible to create drugs that prevent APOE variants from bonding to the sugar-protein compound, Belluck reports.

    However, if it is successful, it would be years before a new drug would hit the market because researchers must first test the treatment in animal and human brains (Belluck, New York Times, 11/4).

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