Francisco Lopera, a neurologist at the University of Antioquia in Medellin, Colombia, has been painstakingly collecting brains, birth and death records from one sprawling Colombian family to study Alzheimer’s.Credit…Federico Rios Escobar for The New York Times
A woman with lots of beta-amyloid buildup (red) in her brain remained cognitively healthy for decades.
by Kelly Servick
In 2016, a 73-year-old woman from Medellín, Colombia, flew to Boston so researchers could scan her brain, analyze her blood, and pore over her genome. She carried a genetic mutation that had caused many in her family to develop dementia in middle age. But for decades, she had avoided the disease. The researchers now report that another rare mutation—this one in the well-known Alzheimer’s disease risk gene APOE—may have protected her. They can’t prove this mutation alone staved off disease. But the study draws new attention to the possibility of preventing or treating Alzheimer’s by targeting APOE—an idea some researchers say has spent too long on the sidelines.
“This case is very special,” says Yadong Huang, a neuroscientist at the Gladstone Institutes in San Francisco, California, who was not involved with the research. “This may open up a very promising new avenue in both research and therapy.”
APOE, the strongest genetic risk factor for Alzheimer’s, has three common forms. A variant called APOE2 lowers risk of the disease. The most common variant, APOE3, doesn’t influence risk. APOE4 raises risk; roughly half of the people with the disease have at least one copy of this variant.
Researchers have long contemplated targeting APOE with therapies. A team at Cornell University will soon start a clinical trial that infuses the protective APOE2 gene into the cerebrospinal fluid of people with two copies of APOE4.
But mysteries about APOE have kept it from becoming a front-runner among drug targets. “It does so many things that it’s confusing,” says Eric Reiman, a neuroscientist at the Banner Alzheimer’s Institute in Phoenix and a co-author on the new paper. The APOE protein binds and transports fats and is abundant in the brain. And the APOE4 variant seems to encourage the formation of sticky plaques of the protein beta-amyloid, which clog the brain in Alzheimer’s. But powerful amyloid-busting drugs have repeatedly failed to benefit patients in clinical trials. Some researchers saw no reason to try an APOE-targeting therapy that seemed to be “just a poor man’s antiamyloid treatment,” Reiman says.
The Colombian woman’s case suggests other ways APOE could affect Alzheimer’s risk. The woman participated in a study led by researchers at the University of Antioquia in Medellín that has tracked roughly 6000 members of her extended family. About one-fifth of them carried an Alzheimer’s-causing mutation in a gene called presenilin 1; these carriers generally developed dementia in their late 40s. Yet the woman didn’t show the first signs of the disease until her 70s, even though she, too, carried the mutation. “She’s definitely an outlier,” says cell biologist Joseph Arboleda-Velasquez of Harvard Medical school in Boston. (The research team is keeping the woman’s name confidential to protect her privacy.)
In Boston, a positron emission tomography scan of the woman’s brain revealed more amyloid buildup than in any other family member who has been scanned. “It was very striking,” says Yakeel Quiroz, a clinical neuropsychologist at Massachusetts General Hospital and Harvard Medical School. But the team found no signs of major damage to neurons, and minimal buildup of another Alzheimer’s hallmark: the misfolded protein tau. Whatever protection this woman had didn’t depend on keeping the brain amyloid-free. Instead, her case supports the idea that tau has a “critical role … in the clinical manifestations of Alzheimer’s disease,” says Jennifer Yokoyama, a neurogeneticist at the University of California, San Francisco.
Genome sequencing revealed two copies of a rare mutation in the APOE gene, the researchers report this week in Nature Medicine. First discovered in 1987, the mutation, known as Christchurch, occurs in a region separate from those that determine a person’s APOE2, 3, or 4 status. (The woman has the neutral APOE3 variant.) Previous research found that the Christchurch mutation—like the more common protective APOE2 mutation—impairs APOE’s ability to bind to and clear away fats and sometimes leads to cardiovascular disease.
The researchers also found that the mutation prevents APOE from binding strongly to other molecules called heparan sulfate proteoglycans (HSPGs), which coat neurons and other cells “like a carpet,” says Guojun Bu, a neuroscientist at the Mayo Clinic in Jacksonville, Florida, who has studied the interaction between these molecules and APOE.
APOE2 may also impair the protein’s ability to bind HSPGs. But how that could protect against disease isn’t clear. One possible clue: Research by neuroscientist Marc Diamond of the University of Texas Southwestern Medical Center in Dallas and his colleagues suggest the toxic tau protein relies on HSPGs to help it spread between cells. Maybe the less APOE binds to HSPGs, the harder it is for tau to spread.
But, Diamond cautions, “It will require much more study to understand if this relationship exists.” The Christchurch mutation might have protective effects unrelated to HSPGs; it’s also possible that mutations other than Christchurch protected the woman.
If hampering APOE’s normal binding really staved off her Alzheimer’s, future treatments might aim to mimic that effect. An antibody or small molecule could latch onto the APOE protein to interfere with binding, gene editing could change the structure of APOE to imitate the Christchurch variant, or a “gene silencing” approach could reduce production of APOE altogether.
Reiman hopes the new study will rally researchers to pursue treatments related to APOE. He, Quiroz, Arboleda-Velasquez, and other collaborators also posted a preprint on the medRxiv server on 2 November showing that people with two copies of APOE2 have lower Alzheimer’s risk than previously thought—about 99% lower than people with two copies of APOE4. “When it comes to finding a treatment that could have a profound impact on the disease,” Reiman says, “APOE may be among the lowest hanging fruit.”