Mutation Linked to Alzheimer’s Resistance Discovered

Researchers have discovered a Colombian woman who, despite her and thousands of her relatives having genes has been linked to them developing Alzheimer’s disease by the age of 50, did not develop Alzheimer’s until her 70s. This led researchers to the question of why. 

The woman, whose name was not revealed for privacy reasons, is a member of an extended family that resides in Medellin, a large city in a valley of the Andes mountains. The family consists of about 6,000 people. They have been afflicted with dementia for centuries, and it is known as “La Bobera” or “the foolishness.”

Decades ago, neurologist Dr. Francisco Lopera began collecting data from members of the family, their birth and death records, and their painstakingly acquired brains. Through his collection of what is now 300 brains, Dr. Lopera helped discover their Alzheimer’s was caused by a specific mutation on the gene Presenilin 1.

When researchers found the woman had this mutation but showed no signs of cognitive impairment, they sent her to Boston for brain scans and other tests. Neuropsychologist Dr. Yakeel Quiroz said the results were puzzling.

The woman’s brain showed the foremost indication of Alzheimer’s, detected with brain scans. There was a clear buildup of amyloid protein. In fact, according to Dr. Quiroz, she had the “highest level of amyloid that we have seen so far.” The excess probably accumulated because she had lived so much longer than Alzheimer’s-suffering family.

Other than that, she didn’t show much evidence of the disease. There was little atrophy of her brain. Also, there was only a little bit of the protein tau, which forms tangles that result in many different diseases, including Alzheimer’s. She was in considerably better condition than patients who were 20 years younger.

Dr. Quiroz consulted cell biologist Dr. Joseph Arboleda-Velazquez and determined the woman has a mutation on a common gene called APOE.

APOE is already known to have a link with Alzheimer’s. One variation, APOE4, is present in 40% of Alzheimer’s patients. Another variation, APOE3, is the one the woman has, similar to many of her family members who still developed the disease at the same age like everyone else. However, she has two copies of this gene, thanks to a mistake at some point in her DNA sequencing.

There is a rare mutation that sometimes occurs with the APOE. This mutation is called the Christchurch mutation (named after the New Zealand city in which it was discovered). The mutation reduces the amount of binding of the gene to a particular sugar-protein. This binding has a direct link to the spread of tau in Alzheimer’s; the more binding, the more likely a person is to develop the disease. Because this mutation reduces the amount of binding, those with the mutation are less likely to develop Alzheimer’s.

So the woman has this rare mutation, that is less rare in her family than the general population. But, as it was stated, those in her family that had this gene still developed the disease. So why didn’t she?

The answer lies in her coincidental, accidental duplication of this gene. Because the gene is duplicated, the effects of the mutation are duplicated. She has two Christchurch mutations, so she has twice the protection against Alzheimer’s it provides.

This offered insight into Alzheimer’s treatment after researchers were able to create a compound that mimicked the effect of this mutation. It worked in laboratory dish experiments, suggesting it could work in future drugs.

Dr. Arboleda-Velazquez explained why this patient is so important.

“We’ve learned that at least one individual can live for very long having the cause of Alzheimer’s, and she’s resistant to it,” he said. “What this patient is teaching is there could be a pathway for correcting the disease.”