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Colombian family's genes offer new clue to delaying onset of Alzheimer's

Dr. Francisco Lopera, left, of the University of Antioquia, confers with fellow researcher Yakeel Quiroz of Massachusetts General Hospital. (Massachusetts General Hospital) Dr. Francisco Lopera, left, of the University of Antioquia, confers with fellow researcher Yakeel Quiroz of Massachusetts General Hospital. (Massachusetts General Hospital)
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Scientists studying a family plagued by early-in-life Alzheimer’s found some carry a genetic oddity that delays their initial symptoms by five years.

The finding points to novel ways of fighting the mind-robbing disease – if researchers can unravel how a single copy of that very rare gene variant offers at least a little protection.

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

The first hint of this genetic protection came a few years ago. Researchers were studying a huge family in Colombia that shares a devastating inherited form of Alzheimer’s when they discovered one woman who escaped her genetic fate. Aliria Piedrahita de Villegas should have developed Alzheimer’s symptoms in her 40s but instead made it to her 70s before suffering even mild cognitive trouble.

The big clue: She also harbored something incredibly rare, two copies of an unrelated gene named APOE3 that had a mutation dubbed Christchurch. That odd gene pair appeared to shield her, staving off her genetic predisposition for Alzheimer's.

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

Neuropsychologist Yakeel Quiroz poses for this undated selfie in front of a imaging screen. (Yakeel Quiroz via AP)

But would one copy be enough to offer any protection? Those Christchurch carriers on average showed their first signs of cognitive trouble at age 52, five years later than their relatives, concluded a collaboration that includes Mass General Brigham researchers and Colombia's University of Antioquia.

The findings, 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 that modifying one of the copies could be really helpful,” at least in helping to delay the disease, he said.

Already some very early work is beginning to explore if certain treatments might induce the protective mutation, he added.

More than six million Americans, and an estimated 55 million people worldwide, have Alzheimer’s. Less than one per cent of cases are like the Colombian family’s, caused by a gene passed through generations that triggers the disease at unusually young ages.

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

Then came discovery of the Christchurch variant’s seemingly protective role.

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

Wednesday's study included brain scans from two people with a single Christchurch copy and autopsy analysis of four others who’d died. Quiroz cautioned there's still a lot to learn about how the rare variant affects the underlying Alzheimer’s process — including whether it affects the common old-age type — but said tau and inflammation are among the suspects. 

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