Researchers have discovered a rare genetic trait that could delay the onset of Alzheimer’s in people who face an overwhelming risk of developing the mind-robbing disease.
A study published Wednesday in The New England Journal of Medicine reported that 27 people from an extended Colombian family who carried a genetic variant called Christchurch developed Alzheimer’s disease several years later than expected. The findings build on early research in 2019 from a unique family predisposed to pass on the disease. The researchers found that a woman who had the same genetic trait delayed the onset of Alzheimer’s by about three decades.
Scientists from Mass General Brigham believe the evidence could be used to develop an Alzheimer’s drug or medication that replicates the protective effects of the Christchurch genetic variant.
“We have enough evidence, and now the focus should be on trying to leverage this discovery to our therapies,” said Dr. Joseph Arboleda-Velasquez, a scientist at Mass General Brigham who co-authored the study. The aim is huge, he said: “How can we learn from the protective effects of Christchurch to develop new therapies that will help everybody?”
Why did researchers focus on a family in Colombia?
The research was isolated to South America where the participants worked with a rare set of data. More than 1,000 members of an extended family in Colombia carry a genetic mutation that puts them at near certain risk of developing early-onset Alzheimer’s disease. The symptoms usually begin when the relatives are in their mid-40s. The mutation carriers are part of an extended family of about 6,000 people who live in and around Medellin, Colombia. In the 1980s, a University of Antioquia neurologist, Francisco Lopera, discovered the family had been afflicted with this inherited mutation, passed from generation to generation, for decades. Using advances in genetic testing, doctors identified the inherited mutation that triggered early-onset Alzheimer’s in these family members. It was called the Paisa mutation, named after the inhabitants of the region.
What did this study examine?
From 1995 through 2022, researchers from the University of Antioquia in Medellin collected detailed information about the family members who participated in a series of medical studies. The family members underwent medical exams, genetic testing and neuropsychological assessments.
Researchers examined detailed information of family members who carried the Paisa mutation. Researchers knew the Paisa mutation carriers typically developed memory and thinking problems in their mid-40s and typically died more than a decade later.
In 2019, researchers discovered a woman who carried the Paisa mutation and did not experience symptoms of Alzheimer’s until she reached her 70s – about three decades later than the symptoms have typically appeared among Paisa mutation carriers. Genetic testing revealed this woman also had two copies of the Alzheimer’s gene APOE3 variant, called the Christchurch variant.
In the study published this week, researchers examined whether Christchurch offered extra protection to people who also have the Paisa mutation. They found 27 people with the Paisa mutation and one copy of the Christchurch variant. Those individuals preserved normal memory and thinking longer than a comparable group who just had the Paisa mutation.
The group that only had Paisa showed signs of disease at a median age of 47, while people who carried Christchurch and Paisa did not exhibit memory and thinking problems until they were 52 – five years later.
Yakeel T. Quiroz, a study co-author and clinical neuropsychologist and neuroimaging researcher at Massachusetts General Hospital, said the research findings “suggest the potential for delaying cognitive decline and dementia in older individuals.”
Quiroz added the findings can be used to develop effective treatments to prevent Alzheimer’s dementia.
What’s next for drug development?
Arboleda-Velasquez, who works as a Harvard Medical School associate professor of ophthalmology, said his laboratory is using these study findings to develop potential antibody drugs to combat Alzheimer’s disease.
His goal is to begin testing medications in human clinical trials by 2026.
Eric Reiman, executive director at Banner Alzheimer’s Institute in Phoenix and a co-author of the study, said the study bolsters the “idea that this rare variant of the major genetic risk factor for Alzheimer’s disease plays a protective role in the development of Alzheimer’s.”
Reiman said further research is needed into the underlying role of APOE on hallmarks of the disease, including beta-amyloid plaques and tau tangles found in Alzheimer’s patients.
The Christchurch study “provides further support for the idea of targeting APOE in the treatment and potential prevention of Alzheimer’s disease.”
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