The town of Yarumal in Colombia is famous, but not for an uplifting reason: It has the world’s largest population of people with Alzheimer’s disease.

In Yarumal and the surrounding state of Antioquia, an estimated 5,000 people carry a gene mutation that causes an early-onset form of Alzheimer’s. Half of those people will be diagnosed by age 45, and the other half will develop the disease by the time they are 65.

Locals call the disease La Bobera — “the foolishness” — and the village bears uncanny parallels with the fictional Macondo in Gabriel García Márquez’s novel “One Hundred Years of Solitude,” where people suffer memory disorders and hallucinations. While what is sometimes called Yarumal’s curse has been well known, no one has known how the mutation first appeared.

Now researchers have traced the ancestry of the mutation, concluding that it was probably introduced by a Spanish conquistador early in the 17th century.

Ken Kosik at the University of California at Santa Barbara led a group that collected blood samples from 102 people in Antioquia and sequenced their genomes. E280A, the mutation causing Yarumal’s form of early-onset Alzheimer’s, was found in 74 individuals.

Because Kosik’s team also had information on the genome sequence around the mutation, they could use something called identity-by-descent analysis to determine how the people in the study were related. The analysis suggested the mutation arose from a common ancestor around 375 years ago.

Genetic profile

The researchers compared the genetic profile of an Antioquian carrier of E280A against genetic profiles from three potential continents of origin, and the evidence pointed to Western Europe.

This is consistent with Spanish origin for the 17th-century carrier of the initial mutation, the team says. The conquistadors — soldiers and explorers of the Spanish Empire — began colonizing Colombia in the early 16th century; Yarumal itself was founded in 1787.

“It’s hard to explain why all these people would share such a large chunk of DNA if there hadn’t been a common founder,” Kosik says.

“Putting the genetic data and the historical records together, the assumption that the mutation was introduced by one Spanish conquistador is very likely,” says Rita Guerreiro, a geneticist at University College London. “I think it is fair to conclude from this study that the history of Yarumal and the history of E280A are one and the same.”

A factor that complicates trials of possible preventive treatments for Alzheimer’s is that the drugs are tested on people already exhibiting signs of the disease. Yarumal is one of few places in the world where researchers can be sure that a sizable proportion of people will develop Alzheimer’s. Thus, there is an ethical rationale for testing such drugs on Yarumal residents before they show symptoms.

One of the problems with diagnosing Alzheimer’s at an early stage is that it requires a hospital and a lengthy, expensive procedure to look for signs of amyloid plaques in the brain.

“What is needed is a simple memory test that can be carried out by a nurse on a home visit,” says Mario Parra, of Herriot Watt University in Edinburgh, Scotland. Parra and colleagues are developing just such a test and have used it in Antioquia.

To know or not

The people recruited for genome sequencing in Antioquia were not told whether they carry the E280A mutation. “We made a decision, with a great deal of agony, that we wouldn’t tell them, as there are no genetic counselors over there,” Kosik says.

To illustrate the importance of counseling, Kosik recalled a conversation he’d had with a young man. “There was a 24-year-old kid who said he’d want to know the outcome of his test. ‘But there’s no treatment,’ we said. The boy put his hand in the shape of a gun to his head.”

The young man was indicating that he would kill himself, even though if he does have the mutation his symptoms will not appear for at least two decades. Another person, a woman of 28, came to the researchers saying she wanted to have children but was afraid of passing on the gene.

Kosik says he sometimes thinks that the decision not to tell participants their genetic status was a good one but that perceptions about genetic testing are changing and the practice of not telling participants will be difficult to sustain.

James Pickett, head of research at Britain’s Alzheimer’s Society, was encouraged by Kosik’s discovery. “There’s been a lack of clinical trials looking at inherited Alzheimer’s disease, so new research that helps us to understand the origins of a genetic mutation across generations is interesting,” he says.

New Scientist