But she was just one patient, which left one question unanswered: Could this case hold the key to new ways to prevent Alzheimer’s? Or was she a one-off?
According to a study published Wednesday, New England Journal of MedicineThe researchers reported that 27 people from the same large Colombian family who also had a genetic risk for Alzheimer’s disease and carried one copy of the Christchurch gene, and that cognitive decline was delayed by about five years in this particular group, suggesting that drugs that mimic the gene may have a similar effect.
“In medicine, we’re taught to be careful not to draw too many conclusions from one patient,” says co-author Joseph F. Arboleda Velásquez, an associate scientist at Massachusetts Eye and Otolaryngology in Boston. The study concluded: “It may have to do with what she ate, or didn’t eat. It may have to do with the water in her home. The fact that we found 27 people, some of whom lived in urban areas and some in rural areas, increases our confidence in the findings and shows that the results are replicable.”
Key insights from low-dose protection
Francisco Lopera, a neurologist at the University of Antioquia in Medellín, Colombia, began treating patients with a progressive, genetic form of Alzheimer’s disease 40 years ago.
Cognitive impairment began in the mid-40s, full-blown dementia developed by age 50, and the patient died in his 60s. Researchers have traced the cause of the disease to a mutation in the presenilin 1 gene, and it is now known that approximately 1,200 members of a large family are affected.
Piedrahita de Villegas has shown scientists that it’s possible to defy this dire genetic fate, but for exceptional patients to translate into broader medical insights, scientists need confirmation that the genes produce beneficial effects and can have the same effect in others.
People have two copies of the APOE gene, one inherited from each parent, and having two copies of the Christ Church version, as Piedrahita de Villegas did, is “rare, extremely rare,” says Yakiel T. Quiroz, a clinical neuropsychologist at Massachusetts General Hospital, so researchers began looking for people who had just one.
A man with an Alzheimer’s risk mutation and a copy of the Christchurch gene provided the first clue. When he was diagnosed with mild cognitive impairment at age 51, brain imaging showed that his brain He had elevated levels of plaques of the beta-amyloid protein, a telltale sign of Alzheimer’s disease, but intriguingly, he had limited tangles of another Alzheimer’s-associated protein called tau, and developed mild dementia at age 54, many years later than expected.
“This was a signal that having one copy might have been protective,” Quiroz said. The team found 26 patients with this genetic makeup. Not all of them developed cognitive impairment, but those who did had delayed symptoms, starting five years later than patients without Christchurch. Dementia onset was also delayed by four years.
The discovery that one copy of the Christchurch gene provides some protection is a ray of hope for scientists working to develop a treatment. Requiring two copies could make the bar for any new drug prohibitively high: it would have to be extremely effective to have any effect. But the fact that smaller amounts of the gene can prevent the disease from developing is a good sign, suggesting that mimicking even part of how the Christchurch gene works might be effective.
“This is really an important study and the results are very meaningful,” said Yadong Fan, director of the Center for Translational Advancement at the Gladstone Institutes, an independent biomedical research organization based in San Francisco. His lab, which was not involved in the study, last year Christchurch Mutation The technique has been shown to work in mice prone to Alzheimer’s and in human brain cells in a dish, but he noted that there has been a significant knowledge gap about how it might affect people in the real world.
Rare patients pave the way for new treatments
For years, Alzheimer’s research has focused on removing the sticky amyloid plaques that build up in the brain. Some treatments have been successful, but a cure is far from possible. New research points to the potential of a different biological target: drugs that mimic the rare Christchurch variant of the APOE gene.
John Hardy, a neurogeneticist at the UK Dementia Institute at University College London, said drug companies have not been very enthusiastic about APOE because it is a difficult target, but that is changing.
“Interest is growing and this discovery is part of the reason why,” Hardy said in an email.
As a next step, the researchers Experimental antibody drugs When the Christchurch-mimicking drug was administered to mice genetically engineered to develop hallmarks of Alzheimer’s disease, the researchers found that it reduced the buildup of tangles of the tau protein — a sign that the mice were on the right track.