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  • Posted June 20, 2024

Colombian Family's Genes Could Hold Key to Delaying Alzheimer's

A Colombian family’s genetics are shining a spotlight on a gene that might help protect people from the ravages of Alzheimer’s disease.

About 1,200 out of 6,000 family members carry a genetic variant called the “Paisa mutation,” which dooms them to early Alzheimer’s, researchers said.

But 28 family members with the Paisa mutation dodged early Alzheimer’s, apparently because they carry another gene that protects against the degenerative brain disease, researchers reported June 20 in the New England Journal of Medicine.

The study represents the first evidence that having this other gene -- known as the “Christchurch variant” -- might confer some protection against inherited Alzheimer’s, researchers said.

Drugs and therapies focusing on this genetic pathway might be capable of preventing or treating dementia and Alzheimer’s in others, said co-lead author Yakeel Quiroz, director of the Familial Dementia Neuroimaging Lab at Massachusetts General Hospital.

“As a clinician, I am highly encouraged by our findings, as they suggest the potential for delaying cognitive decline and dementia in older individuals,” Quiroz said in a hospital news release. “Now we must leverage this new knowledge to develop effective treatments for dementia prevention.”

The study focused on variants of the apolipoprotein E (APOE) gene.

The APOE4 variant is known to increase the risk of Alzheimer’s, and is linked to developing a more severe form of dementia, according to the Mayo Clinic.

On the other hand, the APOE3 gene variant has until now not seemed to have any affect on the risk of Alzheimer’s.

But in 2019, researchers found that a woman in the Colombian family who carried two copies of a specific APO3 variant developed cognitive impairment three decades later than expected.

Most people with the Paisa mutation develop mild cognitive impairment in their 40s, dementia in their 50s and die from dementia complications in their 60s.

But this woman carried the APO3 “Christchurch” variant, and subsequently didn’t develop brain problems until her late 70s.

For the new study, researchers dug into the medical history of the Colombian family to see if any other members benefited from the Christchurch variant.

Analyzing nearly 1,100 descendants of the Colombian family, researchers identified 27 additional members who carried one copy of the Christchurch variant as well as the Paisa mutation.

These 27 family members all experienced delayed onset of dementia and Alzheimer’s.

They began showing signs of cognitive impairment at age 52, on average, compared to age 47 for family members without the Christchurch variant. They also showed signs of dementia four years later than other relatives.

This is important because it shows that preventing Alzheimer’s through the Christchurch variant is possible, said co-senior study author Dr. Joseph Arboleda-Velasquez, an associate scientist at Mass Eye and Ear.

“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," Arboleda-Velasquez said.

“Our new study is significant because it increases our confidence that this target is not only protective, but druggable,” Arboleda-Velasquez added. “We think that therapeutics inspired by protected humans are much more likely to work and to be safer.”

Brain scans and autopsies showed that people with the Christchurch variant had healthier blood vessels, lower levels of tau protein and preserved activity in brain regions typically involved in Alzheimer’s disease.

Further studies involving larger and more ethnically diverse groups could shed more light on the protective effect of the Christchurch variant, and determine if it could translate into treatments for Alzheimer’s, the researchers concluded.

“As a next step, we are currently focused on improving our understanding of the brain resilience among the remaining family members who carry one copy of the Christchurch variant,” Quiroz said. “This involves conducting structural and functional MRI scans and cognitive evaluations, as well as analyzing blood samples to assess their protein and biomarker profiles.”

More information

The Mayo Clinic has more about the genetics of Alzheimer’s disease.

SOURCE: Mass General Brigham, news release, June 19, 2024

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