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Rare genetic mutations protected a woman from developing Alzheimer’s

Katherine Ellen Foley
A single yellow flower blooms among grey ivy.

Most of the time when we think about genetic mutations, we think about the ones that spell disaster. But sometimes, our genes can have the opposite effect: Instead of increasing our risk for certain diseases, they can protect us from them.

This has turned out to be the case with a Colombian woman in her 70s. By all indications, she should have developed Alzheimer’s disease by her mid-40s. She has one of three rare mutations that lead to early-onset Alzheimer’s disease—people with this mutation only make up about 1% the 44 million individuals living with Alzheimer’s globally. And yet, by the time she turned 70 she was still mostly healthy; although she has developed mild cognitive impairment, which can be a warning sign for Alzheimer’s, she may never experience dementia.

The reason for her continued health? A super rare mutation to both copies of another gene related to Alzheimer’s, called APOE. Called the Christchurch mutation (for the town in New Zealand where scientists discovered it in the 1980s), it seems to somehow counteract the risk of Alzheimer’s disease—and could inspire future treatments or preventions for it. Researchers in the US and in Colombia published the woman’s case study on Monday, Nov. 4 in the journal Nature Medicine.

The woman, who is still alive and living in Colombia, comes from a family where dominantly-inherited Alzheimer’s is common. She and some 6,000 members of her kindred participate in the Colombia Alzheimer’s Prevention Registry, which is run by Francisco Lopera, a neurologist at the University of Antioquia in Colombia. Some 1,200 people in the registry have a mutation that causes them to over-produce amyloid protein in the brain, one of the hallmark signs of the disease. Everyone in the registry can enroll in clinical research trials for Alzheimer’s.

This particular woman, however, never got sick. When researchers maintaining the registry noticed that it took her three decades to even develop mild cognitive impairment, they flew her to Boston, where she agreed to let researchers at Harvard University conduct a series of tests.

What they found in her brain imaging shocked them. “She had the highest amyloid beta burden of anyone else in the cohort,” says Eric Reiman, a neurologist with the Banner Alzheimer’s Institute in Arizona, who co-authored the paper. This was consistent with her dominantly-inherited Alzheimer’s mutation. Normally, these high levels of amyloid are thought to lead to buildups of another deformed protein, called tau, along with inflammation and the ultimate destruction of neurons.

But the woman didn’t have the characteristic tangles of tau. And the regions of her brain that are most commonly affected by Alzheimer’s still seemed to be working just like they would in an otherwise healthy adult.

When they sequenced her whole genome, researchers found that her APOE gene had two copies of the Christchurch mutation: a single basepair switch that tweaks the protein produced by the gene. Somehow, this tweaked version of the protein seemed to mitigate the effects of the extra amyloid in her brain.

That means targeting these downstream effects, in addition to amyloid itself, may be a viable treatment for Alzheimer’s—although it’s not clear how to go about that just yet. The vast majority of drug trials targeting amyloid have failed, with the notable exception of one trial from the drug company Biogen that appears to have had positive results. Having more targets increases the likelihood of having more successful treatments that work for more people, or even combination therapies.

This case study “leads us to think about the importance of such studies in relatively understudied populations,” says Nilufer Ertekin-Taner, a neurogeneticist with the Mayo Clinic in Jacksonville, Florida, who was not involved with the study. Scientific knowledge of the Christchurch mutation suggests that it’s incredibly rare, but that could be because the majority of research on Alzheimer’s and dementia has been done on white populations. By including more diverse populations in future research, scientists can get a better idea of how this mutation works in other healthy populations—and ultimately, how it could mitigate the disease overall.

Correction (Nov. 4): An earlier version of this story accidentally mis-named Eric Reiman as Dan Reiman.

 

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