Researchers have discovered a rare genetic trait that may delay the onset of Alzheimer’s disease in people who face an overwhelming risk of developing the mind-destroying illness.
A large Colombian family of 27 people with a genetic mutation known as Christchurch developed Alzheimer’s disease several years later than expected, according to a study published Wednesday in the New England Journal of Medicine. The findings build on earlier research from 2019 that looked at a unique family predisposed to inheriting the disease. Researchers found that women with the same genetic trait delayed the onset of Alzheimer’s by about 30 years.
Scientists at Massachusetts General Hospital at the Brigham believe this evidence could be used to develop Alzheimer’s drugs and medications that mimic the protective effects of the Christchurch gene mutation.
“We have enough evidence now that the focus should be on translating these findings into treatments,” said study co-author Dr. Joseph Arboleda Velazquez, a scientist at Massachusetts General Hospital and Brigham Hospital. The goal, he said, is ambitious: “How can we learn from Christchurch’s preventive effects and develop new treatments that can help everyone?”
Why did researchers focus on Colombian families?
The study was limited to South America, where participants worked with a rare dataset. More than 1,000 members of an extended Colombian family carry a genetic mutation that puts them at almost certain risk for developing early-onset Alzheimer’s disease. Symptoms usually begin when relatives are in their mid-40s. The mutation carriers are part of an extended family of about 6,000 people living in and around Medellín, Colombia. In the 1980s, Francisco Lopera, a neurologist at the University of Antioquia, discovered that the family was plagued by this genetic mutation that had been passed down from generation to generation for decades. Taking advantage of advances in genetic testing, doctors identified the genetic mutation that caused early-onset Alzheimer’s disease in members of these families. It was called the Paisa mutation, after the inhabitants of the region.
What did this study investigate?
Between 1995 and 2022, researchers from the University of Antioquia in Medellín collected detailed information about families who participated in a series of medical studies. The families underwent medical examinations, genetic testing, and neuropsychological evaluations.
The researchers looked at detailed information about families with the paisa mutation and knew that carriers of the mutation usually develop memory and thinking problems in their mid-40s, and usually die a decade or more later.
In 2019, researchers discovered a woman with the Paisa mutation who didn’t develop symptoms of Alzheimer’s until she was in her 70s — about 30 years later than symptoms typically appear in Paisa mutation carriers. Genetic testing revealed that she had two copies of a mutation in the Alzheimer’s gene, APOE3, called the Christchurch mutation.
In a study published this week, researchers looked into whether Christchurch offered extra protection to people with the Paisa mutation. They found 27 people who carried one copy of the Paisa mutation and one copy of the Christchurch mutation. These people retained normal memory and thinking longer than a comparable group who only carried the Paisa mutation.
While those with only the Paisa gene showed signs of the disease at an average age of 47, those with both the Christchurch and Paisa genes showed no memory or thinking problems until five years later, at age 52.
The findings “suggest potential for slowing cognitive decline and dementia in older adults,” said study co-author Yakiel T. Quiroz, a clinical neuropsychologist and neuroimaging researcher at Massachusetts General Hospital.
Quiroz added that the findings could be used to develop effective treatments to prevent Alzheimer’s disease.
What does the future hold for drug development?
Arboleda Velazquez, an associate professor of ophthalmology at Harvard Medical School, said his lab is using these findings to develop antibody drugs to fight Alzheimer’s.
His goal is to start testing the drug in human clinical trials by 2026.
Eric Reiman, director of the Banner Alzheimer’s Institute in Phoenix and co-author of the study, said the research supports “the idea that this rare variant in a major genetic risk factor for Alzheimer’s disease plays a protective role in the development of Alzheimer’s disease.”
Lyman said further research is needed into APOE’s underlying role in hallmarks of the disease, such as the beta-amyloid plaques and tau tangles seen in Alzheimer’s patients.
The Christchurch study “adds further support to the idea of targeting APOE in the treatment and potential prevention of Alzheimer’s disease.”
