A woman in Colombia with rare genetic resistance to Alzheimer's disease may have more company than scientists thought.
Family members with just a single copy of her version of a particular gene – what's known as the Christchurch variant of apolipoprotein E (APOE) – seem to also be protected against genetically determined early-onset dementia, researchers say, albeit to a far lesser extent.
Aliria Rosa Piedrahita de Villegas was born into a family in Colombia with the largest known incidence of Alzheimer's anywhere in the world.
Among her roughly 6,000 blood relatives, more than 1,000 carry a genetic variant called E280 A, which leads to early development of dementia, or what locals in Colombia call "La Bobera" ("the foolishness"). Cognitive decline can start as early as age 44 but more often begins around age 47.
Like many others in her family, Aliria was a double carrier of the genetic curse, but even as she aged, she described her brain as "golden". Not until she was in her 70s did she begin to show signs of cognitive decline.
A year before her death, scientists announced they'd figured out her secret, with her and her family's willing consent and participation. Aliria was the holder of a rare genetic quirk, involving two copies of the variant APOE3 Christchurch, which seems to postpone the development of Alzheimer's disease.
In 2023, another relative of Aliria's was also found with two copies of the same variant. He, too, defied the odds and did not develop Alzheimer's until his late 60s.
"Our original study told us that protection was possible, and that was an important insight. But if a person needs two copies of a rare genetic variant, it just comes down to luck," explains neuroscientist Joseph Arboleda-Velasquez from the General Brigham hospital for Mass Eye and Ear.
In previous studies, it seemed that one copy of APOE3 Christchurch was not enough to protect against cognitive decline. But that may not be true after all.
The new research compared 27 family members who were genetically predisposed to Alzheimer's with just one APOE3 Christchurch variant against 1,050 members also predisposed to Alzheimer's but who lacked the variant genes altogether. On average, those with a single copy of the variant developed cognitive impairment 5 years later and dementia 4 years later.
That's still much younger than Aliria, but it shows that even a single copy of APOE3 Christchurch can have somewhat of a protective effect.
"Our new study is significant because it increases our confidence that this target is not only protective, but druggable," says Arboleda-Velasquez. "We think that therapeutics inspired by protected humans are much more likely to work and to be safer."
To explore in more detail, brain scans were conducted on two individuals who each carried just one copy for APOE3 Christchurch. Compared to their relatives without this variant, their scans showed reduced tau tangles and sustained metabolic activity, even in the presence of amyloid plaques – a hallmark of Alzheimer's disease.
Furthermore, autopsies from four deceased individuals with the genetic quirk showed blood vessels in the brain with fewer signs of damage.
The study is limited in that it only explores this one genetic predisposition to Alzheimer's disease in a single family. Nevertheless, even in cases of Alzheimer's that are not genetically predetermined, APOE is a gene that keeps popping up, which suggests it's a potential target for drug research.
A variation called APOE4, for example, seems to damage blood vessels in the brain, allowing toxins to more easily accumulate. People with two copies of APOE4 are all but certain to develop Alzheimer's if they live long enough.
"As a neuroscientist, I'm thrilled by our findings because they underscore the complex relationship between APOE and a deterministic mutation for Alzheimer's disease," says clinical neuroscientist Yakeel Quiroz at Massachusetts General Hospital, "potentially paving the way for innovative treatment approaches for Alzheimer's disease, including targeting APOE-related pathways."
The study was published in The New England Journal of Medicine.