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Pioneering Alzheimer’s study in Colombia zeroes in on enigmatic protein

Researchers tracking a genetic mutation that causes an early-onset form of the disease hope to uncover new drug targets.

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Woman from Colombian Alzheimer's study

Elenith is enrolled in a study of people whose families carry a genetic mutation for early-onset Alzheimer's, but she doesn't know whether she will develop the disease. "It has haunted me all of my life but I want to be prepared if possible," she says. Credit: Greg Kendall-Ball/Nature

Medellín, Colombia

Jhon Kennedy was building a house for his family when he realized that his 45-year-old father was beginning to struggle with daily life. His dad tried to help with the construction project but often forgot to complete simple tasks. And he kept getting lost on the way home from work.

Jhon Kennedy wasn’t surprised: his four uncles had also started to lose their memories, one by one. But their doctors in Colombia's rural Antioquia region, which is known for its mountainous terrain and coffee plantations, had never heard of early-onset dementia. It wasn’t until a cousin learned about a study of Alzheimer’s disease at the University of Antioquia in Medellín that Jhon Kennedy’s relatives understood the illness they faced. For more than three decades, researchers there have been tracking a genetic mutation — common in the region — that causes Alzheimer’s to strike people in their 40s and 50s.

Later this year, a team at the university will begin scanning the brains of some Alzheimer’s-study participants with a technique that is available only in a few major medical centres worldwide. It will allow the researchers to track a protein called tau, which accumulates rapidly in the brains of people with the disease as symptoms begin to emerge. Watching tau form in real time could reveal the role it plays in Alzheimer’s, says Francisco Lopera, the neurologist who is leading the research.

Many scientists have long believed that the disease is triggered by another protein, amyloid, that builds up in the brains of people with Alzheimer’s. But several drugs that reduce amyloid levels have failed to relieve the symptoms of the disease in clinical trials, increasing researchers’ interest in the role of tau.

If all goes well, Lopera's team will soon be the first in Colombia with the ability to scan people's brains for tau. The team has already conducted a preliminary imaging study that yielded promising data. In February, he and his colleagues published the results of a pilot trial in which they brought 24 people from the same Colombian family to a facility in Boston, Massachusetts, and used positron-emission tomography (PET) to search their brains for tau. The researchers showed for the first time that tau begins to accumulate in the brains of people with the Antioquia mutation six years before they begin to show signs of disease1.

“This is a very definitive paper,” says Bruce Miller, a behavioural neurologist at the University of California, San Francisco. “I think it’s another piece of evidence that tau is very important and has a strong correlation with clinical symptoms.”

Genetic legacy

The genetic mutation that affected Jhon Kennedy’s father and uncles is famous in the field of Alzheimer’s research. It probably arrived in South America with Spanish conquerors 375 years ago, and now affects 25 extended families in Antioquia with more than 5,000 members. Researchers have published dozens of papers about this group, including some of the clearest proof that amyloid plaques can accumulate in the brain decades before symptoms of Alzheimer’s appear2.

But as questions have emerged about amyloid’s role in Alzheimer’s, researchers have taken a closer look at tau. The protein normally helps to stabilize the structures that allow neurons to communicate with one another. People with Alzheimer’s produce too much dysfunctional tau, causing these structures to collapse into tangles. The amount of the protein seems to increase at the same rate as a person’s symptoms.

In the past several years, researchers have developed radioactive biomarkers that allow them to detect tau in the brains of living people using PET. Studies using the technique have shown that tau accumulation in the brain’s language centres correlates with speech problems, for instance3. Several research groups are beginning clinical trials of drugs that scrub tau from the brain, although this work is at an early stage.

Jhon Kennedy and his 11 siblings each have a 50% chance of inheriting the Alzheimer’s mutation from their father. Eight have enrolled in Lopera’s trial and could be among the first people to have their brains scanned for tau in Colombia. None of the siblings in the study, including Jhon Kennedy, know if they carry the mutation.

Carlos Villegas and lab members at the NeuroBanc in Medellin

The brain lab at the University of Antioquia includes organs from 100 members of a single family who carried a genetic mutation for early-onset Alzheimer's disease.Credit: Greg Kendall-Ball/Nature

Turning to tau

The study, which began in 2013, was designed to test whether crenezumab, a drug that clears amyloid plaques from the brain, could lessen symptoms of Alzheimer’s. Over the past five years Lopera’s team has recruited 252 participants who were between 30 and 60 years old. Those who carry the Alzheimer’s mutation will begin accumulating amyloid in their brains during their early 30s, on average.

Each participant in the trial will receive infusions of crenezumab or a placebo every other week, for five years. Lopera’s team is also testing their cognitive abilities, scanning their brains for amyloid and searching for blood proteins and other biomarkers that could be early indicators of disease.

The researchers hope to begin mapping the tau in participants’ brains in the coming months, once they receive final permission from regulators to produce the crucial radioactive marker, GTP1. When that happens, the team will join a handful of researchers worldwide that are using the technology. “It’s quite remarkable that a population that lives in such a remote area is getting access to some of the most advanced technology for understanding Alzheimer’s,” says Kenneth Kosik, a neuroscientist at the University of California, Santa Barbara.

Lopera and his colleagues want to determine how tau spreads through the brains of young people with Alzheimer’s, and whether that pattern mirrors the distribution of tau seen in elderly people with the disease. They hope to compare their results with data from two clinical trials of anti-amyloid drugs in the United States that have begun scanning participants’ brains for tau. Lopera, Kosik and other scientists are also beginning to identify families in Colombia with different genetic mutations that cause dementia or neurological disorders linked to tau, in the hope of imaging their brains too.

Lopera says that his team will not release any data from the crenezumab trial until it finishes in 2022. But if the results are promising, he adds, the researchers might give the drug to people younger than 30 who carry the mutation for early-onset Alzheimer’s. The scientists have identified nearly 500 young people who might be carriers, including Jhon Kennedy’s 15-year-old daughter. “She’s not worried about it,” Jhon Kennedy says. “She’s like me — she lives day by day.”

Nature 555, 567-568 (2018)

doi: 10.1038/d41586-018-03848-4

Travel for this story was paid for by the Pulitzer Center on Crisis Reporting in Washington DC.

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Updates & Corrections

  • Correction 03 April 2018: This story originally misstated the radioactive marker that will be used in the tau scans. It is GTP1.

References

  1. 1.

    Quiroz, Y. T. et al. JAMA Neurol. http://dx.doi.org/10.1001/jamaneurol.2017.4907 (2018).

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    Reiman, E. et al. Lancet Neurol. 11, 1048–1056 (2012).

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    Ossenkoppele, R. et al. Brain 139, 1551–1567 (2016).

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