But he was just a patient. This left a nagging doubt: Could this be the key to a new way to prevent Alzheimer’s? Or was he once?
In a study published Wednesday in the New England Journal of Medicine, researchers report that 27 members of a Colombian family share a genetic risk of Alzheimer’s, along with a copy from Christchurch. Cognitive decline was delayed in this single group by about five years—suggesting that a drug that mimics the gene could have similar effects.
“In medicine, we’re taught to be careful not to draw too many conclusions from one patient,” said Joseph F. Arbolda-Velasquez, an associate scientist at Mass Eye and Ear in Boston and one of the authors of the paper. From the study, “Maybe it’s related to what he ate or didn’t eat. Maybe something related to the water inside the house. The idea of finding 27 people – some living in the city, some living in rural areas – increases our confidence in the discovery – and shows that the results are replicable.
A key insight into the lower dose of protection
Francisco Lopera, a neurologist at the University of Antioquia in Medellin, Colombia, began caring for patients with aggressive, hereditary Alzheimer’s four decades ago.
Cognitive impairment started when people were in their mid-40s. Complete dementia developed before the age of 50. Patients died in their 60s. The researchers traced the disease to a mutation in the Presenilin 1 gene, which is now known to affect about 1,200 people in an extended family.
Piedrahita de Villegas showed scientists that it is possible to defy this unfortunate genetic fate. But for an exceptional patient to translate into broader medical insight, scientists need to confirm that the gene produces a beneficial effect — and that it can do the same in other people.
People carry two copies of the APOE gene, one of which is inherited from each parent. Yaquil T. Queiroz, a clinical neuropsychologist at Massachusetts General Hospital, said having two copies of the Christchurch version, as Piedrahita de Villegas did, is “rare, very rare.” So they started looking for people with only one person.
A man who carried an Alzheimer’s risk mutation and a copy from Christchurch provided the first clue. Brain imaging at age 51, when he was diagnosed with mild cognitive impairment, showed that his brain Increased levels of beta-amyloid protein plaques, a sign of Alzheimer’s. But interestingly, he had a different Alzheimer’s-related protein called tau, and developed mild dementia years later than expected at the age of 54.
“It was a signal that having a prescription could be protective,” Quiroz said. The team found 26 other people with this genetic makeup. Not all patients develop cognitive impairment, but among those who do, symptoms are delayed and begin five years later than those without CHD. Dementia was also delayed by four years.
The discovery that a copy of Christchurch provides a degree of protection is a promising clue for scientists trying to develop treatments. If two prescriptions were required, the new drug bar might be too much—it would have to be very effective to have any benefit. But observing a lower dose of the gene against the onset of the disease is a good sign. This suggests that even partially mimicking the function of the Christchurch gene can work.
“I think this is a really important study, and the result is very meaningful,” said Yadong Huang, director of the Center for Translational Advances at the Gladstone Institutes, an independent biomedical research organization based in San Francisco. Huang He was not involved in the study, but his lab showed last year that the Christchurch mutation had benefits in Alzheimer’s-prone mice and human brain cells in a dish. However, he noted that until now there has been an important gap in knowledge – how it affects humans in the real world.
Rare patients lead the way to new treatments
For years, Alzheimer’s research has focused on clearing the sticky amyloid plaques that build up in the brain. A few treatments have shown success, but they are far from a cure. A new study shows promise for a different biological target: drugs that mimic the rare Christchurch variant of the APOE gene.
John Hardy, a neurogeneticist at the British Dementia Research Institute at University College London, said pharmaceutical companies had traditionally been less interested in APOE because it was a difficult target, but that was changing.
“Interest is growing, and this finding is part of the reason,” Hardy wrote in an email.
As a next step, researchers have developed an experimental antibody drug that mimics Christchurch’s. When the drug was given to mice genetically engineered to develop Alzheimer’s traits, they found that the drug reduced the accumulation of tau – a sign that they were on the right track.
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