In the fall of 2015, Yakeel Quiroz heard about a woman who defied everything she knew about Alzheimer’s disease. Quiroz, a neuroimaging researcher at Massachusetts General Hospital, has spent more than two decades studying an extended Colombian family with a genetic mutation that causes a devastating younger-onset version of the disease. Every relative with the so-called Paisa mutation experiences la bobera — “the foolishness.” They become forgetful in their mid- to late-30s, struggle with complex tasks and develop mild cognitive impairment in their mid-40s, usually have dementia by their 50s, and typically live for only a decade more.
That fall, Quiroz was on the phone with her collaborator in Colombia, Dr. Francisco Lopera, who has built an Alzheimer’s registry of more than 6,000 members of the family (about half have the mutation). Lopera said a woman had recently enrolled who had the Paisa mutation, which meant “she was supposed to have dementia in her 50s,” Quiroz says. But the woman was in her early 70s and had no signs of memory loss.
Everything they knew about the mutation suggested the woman was unlikely to even live to 70, yet she was healthy and her cognitive tests showed no unusual memory problems. “I couldn’t believe it,” Quiroz says.
The Paisa mutation is uncommon because most cases of Alzheimer’s disease have no single genetic cause. Studying such a high-risk gene can shed light on the more common form of the disease. Quiroz had helped to painstakingly identify and characterize the family’s disease, and she had recently launched the Colombia-Boston Longitudinal Biomarker Study, or COLBOS, to bring carriers of the Paisa mutation to Boston for advanced brain imaging — she runs the Familial Dementia Neuroimaging Lab at MGH. Now she had an opportunity to study a woman whose brain defied her genetic destiny, and see what was keeping her healthy. If they could unlock that mystery, it might help tens of millions of people around the world.
IT TOOK MONTHS to organize the trip from Colombia to Boston and get visas and passports, but in June 2016, the woman — her family has requested she remain anonymous — landed at Logan International Airport. With her were two of her grown children, as well as two bilingual Colombian research assistants who would help shepherd the family around the city for a battery of tests. Lopera, a neurologist at the University of Antioquia, and his team in Colombia had already run initial clinical tests.
Quiroz and her colleagues would create a window into the woman’s brain using positron emissions tomography imaging. The woman would be injected with chemical tracers that would show up on the scans, allowing the researchers to measure two main hallmarks of Alzheimer’s disease: sticky plaques made of a protein called beta-amyloid, which collect between neurons, and fibrous tangles of a protein called tau, which accumulate inside neurons in areas of the brain related to memory. While the Colombian woman had time for a little sightseeing, she spent most of her week inside a clinic. She spent hours receiving two rounds of PET imaging at the MGH main campus, and also had magnetic resonance imaging at the Athinoula A. Martinos Center for Biomedical Imaging in Charlestown. Researchers also did some cognitive tests.
Quiroz’s team needed a couple of weeks to analyze the results. The beta-amyloid tests were done first. The Paisa mutation, which lies in a gene called PSEN-1, causes gradual amyloid buildup beginning at age 28. “She had the highest levels of amyloid (in a brain) that we have seen in somebody from that family,” Quiroz says. Of course, that would be expected from a woman in her 70s with the mutation. But it was also provocative to find a woman with a brain filled with amyloid and no dementia.
When she received the tau test results from her research assistant, Quiroz looked at it and then said to him, “I think you forgot to display the tau pathology.” The images showed large swaths of blue, with few patches of color that would indicate tau buildup. “I thought he had made a mistake,” Quiroz says now. He hadn’t. The score indicating the total level of tau was consistent with those of a much healthier brain. Typically, tau tangles begin to form a decade or so after amyloid plaques, and then rapidly spread. “It’s the first time ever that I saw somebody with really high levels of amyloid with no tau,” Quiroz says.
The MRI of the brain’s structure also showed something inconsistent with Alzheimer’s: The areas of the woman’s brain important for memory had not shrunk significantly. To better understand her brain function, Quiroz arranged for the woman to undergo another kind of PET scan in Colombia, looking to measure the ability of brain cells to drink up glucose, a sign of brain function that has been found to decline with age and to change dramatically in the early stages of Alzheimer’s disease. In that test, Quiroz says, the woman looked as healthy as a much younger person.
She also asked Lopera to run another genetic test, just to be safe. During the woman’s trip to Boston, Quiroz was struck by her conversational ability. “I have seen hundreds of patients who are carriers of the Paisa mutation and they usually struggle to remember conversations when they are in their late 40s,” she notes. This woman was in her 70s and able to remember their daily interactions.
A brain filled with amyloid plaques without severe disease challenged longstanding assumptions in the Alzheimer’s field. For many years, amyloid plaques have been seen as a key driver of the disease — often called the “amyloid hypothesis.” But no drugs targeting amyloid plaques have yet to make it through clinical trials, leading many researchers in search of therapies to focus on tau and other components of the disease.
“Whatever she had was protecting her against tau pathology and against neurodegeneration, which was very remarkable,” Quiroz says. The woman had little formal education or other lifestyle factors that might explain the effect, suggesting the cause might be something in her genes. Quiroz didn’t have the equipment to test this thesis, but she knew someone who did: her husband, Dr. Joseph Arboleda-Velasquez.
HE AND HIS WIFE mostly keep their work lives separate from their family life, says Arboleda-Velasquez, a cell biologist at the Schepens Eye Research Institute of Massachusetts Eye and Ear. But they do discuss interesting developments in their research, and he’d become intrigued with the Colombian case. “It just gave us a hint that if one person can beat [Alzheimer’s], how is that so, and can we learn something about that individual?” he says. With a lab capable of conducting genetic and biological analysis — so-called “wet bench” lab work — he could help investigate those questions. He and Quiroz had worked together tangentially on papers, but “we hadn’t really collaborated very significantly on the Alzheimer’s project before,” he says. “It was just something very exciting and she invited me to work on it.”
His first step was to look for something in the Colombian woman’s genes that distinguished her from her kindred. “Every person has thousands of mutations in the genome, some of them unique that nobody else has,” he says. This meant he would have to winnow through thousands of options to find the one to focus on. Using a specialized software program called Genomizer, they discovered that the woman had a very rare mutation in the gene for apolipoprotein E (APOE), which helps to move cholesterol and fats around the body and throughout the brain, where it also helps regulate the buildup of toxic amyloid and tau. It’s called the Christchurch mutation for the New Zealand city where it was first described.
“I was really excited” to hear this result, says Quiroz, since APOE had already been associated with the common form of Alzheimer’s. The APOE gene has three major variants and one of them, APOE4, strongly increases risk of Alzheimer’s disease. “We thought right away, Perhaps this mutation had something to do with protection,” she says. The research team consulted with other geneticists who supported their instinct, but, “We really needed to do some biochemical work to convince ourselves that this was real,” Arboleda-Velasquez says. That meant experiments to see how the APOE protein produced by the Christchurch mutation interacted with other molecules. One of their main findings was that the Christchurch protein doesn’t stick to a common molecule found on the surface of cells and the tissues that connect them, called heparan sulfate proteoglycans. These molecules have numerous functions, including helping cells send chemical signals back and forth to each other by binding to other molecules. In patients with Alzheimer’s, the molecules are thought to help spread tau tangles throughout the brain. But the Christchurch protein doesn’t connect with them as much as other APOE molecules do. It was possible, then, that the Colombian woman’s mutation had prevented tau tangles from forming.
If the Christchurch mutation had spared one woman from Alzheimer’s, Quiroz and her colleagues wondered, were there others? The team turned to Dr. Ken Kosik, a neurologist at the University of California Santa Barbara and longtime collaborator of Lopera’s. Kosik has built up a database of the Colombian family’s genomes, and his lab found four of them with both the Paisa mutation and the Christchurch mutation in one of their chromosomes. But each of those people had developed Alzheimer’s at a typical age for this family (Quiroz says that research in progress indicates some protection from having one copy of the mutation). The difference was that the woman had two copies of the mutation, one from each parent. “That’s so improbable,” Kosik says.
Quiroz and her collaborators published their work in Nature Medicine last November. Prior to their work, the APOE gene was not seen as a promising area for therapeutic research, in part “because it has a variety of different effects,” says Eric Reiman, a coauthor of the study and executive director of the Banner Alzheimer’s Institute in Arizona.
With a sample of one, Kosik says it’s hard to know whether the double Christchurch mutation protected the woman, but, he says, “It’s a compelling hypothesis.” Arboleda-Velasquez’s lab is working to better characterize the biology of the mutation in cells and animals. It has generated an antibody that mimics the Christchurch mutation’s blocking abilities, and is exploring whether this antibody or one like it could be turned into a drug.
It’s a serendipitous moment, says Reiman, that could not have happened without thousands of patients and family members cooperating with scientists. “Think about all the research volunteers that we study over the years, and the sacrifice they make,” he says. “This shows us how one person can have a profound effect.”
Quiroz echoes his appreciation for the Colombian family. “They actually think of us as partners,” she says. “It’s kind of like we are collaborators; they are invested in the research.” She is planning a virtual symposium in January on APOE biology and treatments. She also continues studying other members of the woman’s family, as well as other patients with the Paisa mutation who have less severe symptoms. Although the COVID-19 pandemic’s impact on travel has meant she’s had to rely on clinical data gathered in Colombia, Quiroz says, her imaging patients have stayed engaged in the research remotely. It’s their best hope for an end to the family’s affliction. Their unusual relative is now in her late 70s and has started showing short-term memory loss.
Courtney Humphries is a journalist and author working on a PhD in environmental sciences at UMass Boston. Send comments to firstname.lastname@example.org.