Scientists studying a family plagued by early-in-life Alzheimer’s have discovered a genetic oddity that delays the onset of symptoms by five years.

Genetic Discovery and Its Implications

The study, published Wednesday, points to novel ways of combating the debilitating disease. If researchers can unravel how a single copy of the rare gene variant offers protection, it could pave the way for new treatments. "It opens new avenues," said neuropsychologist Yakeel Quiroz of Massachusetts General Hospital, who co-led the study. "There are definitely opportunities to copy or mimic the effects."

The Colombian Family Case

The first hint of this genetic protection emerged a few years ago when researchers were studying a large family in Colombia with a devastating inherited form of Alzheimer’s. They discovered one woman, Aliria Piedrahita de Villegas, who defied her genetic destiny. While she should have developed symptoms in her 40s, she did not show even mild cognitive trouble until her 70s.

The big clue lay in her genes: she harbored two copies of an unrelated gene named APOE3 with a mutation dubbed Christchurch. This rare gene pair appeared to shield her from her genetic predisposition for Alzheimer’s.

Extended Family Study

Quiroz’s team then tested over 1,000 extended family members, identifying 27 individuals who carry a single copy of the Christchurch variant. The crucial question was whether one copy could provide any protection. The study found that these carriers showed their first signs of cognitive trouble at an average age of 52, five years later than their relatives without the variant.

This research, conducted in collaboration with Mass General Brigham researchers and Colombia’s University of Antioquia, was published in the New England Journal of Medicine. Dr. Eliezer Masliah of the National Institute on Aging found the findings encouraging. "It gives you a lot of comfort that modifying one of the copies could be really helpful," he said, suggesting that delaying the disease is a significant step forward.

Potential for New Treatments

Already, some early work is beginning to explore if certain treatments might induce the protective mutation. More than 6 million Americans and an estimated 55 million people worldwide suffer from Alzheimer’s. While less than 1% of cases are like the Colombian family’s, caused by a gene that triggers the disease at a young age, the study of these rare cases provides critical insights.

Role of the APOE Gene

Alzheimer’s typically affects people over age 65, with aging being the main risk factor. The APOE gene, which comes in three main varieties, also plays a role. Carrying one copy of the APOE4 gene increases the risk of Alzheimer’s, and having two copies can cause the disease in seniors. Another variety, APOE2, seems to reduce the risk, while APOE3 has long been considered neutral. The discovery of the Christchurch variant’s protective role adds a new layer of complexity to our understanding of APOE.

Understanding the Mechanism

Silent changes in the brain precede Alzheimer’s symptoms by at least two decades, including the buildup of a sticky protein called amyloid, which triggers tangles of another protein, tau, that kill brain cells. Earlier research suggested that the Christchurch variant might impede this tau transition.

The recent study included brain scans from two people with a single Christchurch copy and autopsy analysis of four others who had died. Quiroz emphasized that there is still much to learn about how this rare variant affects the Alzheimer’s process, particularly whether it influences the common old-age type of the disease. Tau and inflammation are among the key areas of investigation.

Wider Implications

The findings underscore the potential for genetic research to reveal new therapeutic targets. Understanding the protective mechanisms of the Christchurch variant could lead to the development of drugs that mimic its effects. Such advancements could be a game-changer in the fight against Alzheimer’s, potentially delaying or preventing the onset of symptoms for millions of individuals worldwide.

Conclusion

This discovery offers a glimmer of hope for developing new treatments that could delay or even prevent Alzheimer’s disease. By understanding the protective mechanisms of the Christchurch variant, researchers may be able to develop therapies that mimic its effects, offering a new strategy in the fight against this devastating disease. The journey to fully understanding and harnessing this genetic protection is ongoing, but the potential impact on millions of lives makes it a crucial area of study. The next steps will involve deeper investigation into the molecular pathways influenced by this rare variant and how they can be targeted therapeutically to benefit a broader population.