Family genes offer new clue for delaying onset of Alzheimer’s disease

Scientists studying a family affected by Alzheimer’s disease early in life have discovered that some of them carried a genetic quirk that delays the appearance of the first symptoms by five years.

This discovery opens the way to new ways to fight this devastating disease – if researchers can understand how a single copy of this very rare genetic variant offers at least some protection.

“This opens up new avenues,” said neuropsychologist Yakeel Quiroz of Massachusetts General Hospital, who helped lead the study published Wednesday. “There are certainly opportunities to copy or imitate the effects.”

The first indications of this genetic protection appeared a few years ago. The researchers were studying a huge family in Colombia who shares a devastating hereditary form of Alzheimer’s when they discovered a woman who had escaped her genetic fate. Aliria Piedrahita de Villegas should have developed symptoms of Alzheimer’s disease in her 40s, but instead reached her 60s before experiencing even mild pain. cognitive disorders.

The big clue: It also harbored something incredibly rare, two copies of an unrelated gene called APOE3 that had a mutation called Christchurch. This strange pair of genes seemed to protect her, repelling her genetic predisposition to Alzheimer’s disease.

Quiroz’s team then tested more than 1,000 extended family members and identified 27 carrying a single copy of this Christchurch variant.

But would a single copy be enough to offer any protection? These Christchurch carriers showed their first signs of cognitive impairment on average at age 52, five years later than their relatives, concluded a collaboration including researchers from Mass General Brigham and Colombia’s University of Antioquia.

The results, published in the New England Journal of Medicine, are encouraging, said Dr. Eliezer Masliah of the National Institute on Aging.

“It gives you a lot of comfort knowing that changing one of the copies could be really helpful,” at least in helping delay the disease, he said.

Very preliminary work is already beginning to determine whether certain treatments could induce the protective mutation, he added.

More than 6 million Americans and approximately 55 million people worldwide suffer from Alzheimer’s disease. Less than 1% of cases resemble those of the Colombian family, caused by a gene passed down through generations triggers illness at an unusually young age.

Alzheimer’s disease is typically a disease that affects people over the age of 65, and while simply getting older is the main risk, the APOE gene has long been known to play a role. It comes in three main varieties. Carrying one copy of the famous APOE4 gene increases your risk – and recent research has shown that having two copies of APOE4 can actually cause Alzheimer’s disease in older people. Another variety, APOE2, appears to reduce risk while APOE3 has long been considered neutral.

Then came the discovery of the apparently protective role of the Christchurch variant.

Silent changes in the brain precede Alzheimer’s symptoms by at least two decades, including the buildup of a sticky protein called amyloid that, once it reaches certain levels, appears to trigger tangles of another protein, called tau, which kills brain cells. Previous research has suggested that something in the Christchurch variant hinders this tau transition.

Wednesday’s study included brain scans of two people with a single copy from Christchurch and autopsy analysis of four other people who died. Quiroz cautioned that there was still much to learn about how the rare variant affects the underlying process of Alzheimer’s disease – including whether it affects the common type of old age – but said the Tau protein and inflammation were among the suspects.