A man who defied genetics for decades may hold a clue to preventing Alzheimer’s disease, scientists say

CNN
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Researchers working to unlock the secrets of Alzheimer’s disease say they’ve received a major clue that could help protect those at risk for this type of dementia.

A man who seemed destined to develop memory loss in his 40s or 50s, based on family history, maintained normal functioning for decades longer than he should have. It appears to have been protected by a rare genetic modification that improved the function of a protein that helps nerve cells communicate.

Scientists say understanding how this genetic change defended his brain could help prevent Alzheimer’s disease in other people.

The man is part of a large family in Antioquia, Colombia, many of whose members have inherited a mutated gene called presenilin-1, or PSEN1. Carriers of PSEN1 are almost certain to develop Alzheimer’s disease at a relatively young age.

The man, who had the PSEN1 mutation, eventually developed memory and thinking problems. He was diagnosed with mild dementia at the age of 72, then experienced memory decline and an infection. He died of pneumonia at age 74.

But by all indications, he should have had memory and thinking problems decades earlier. When doctors examined his brain after his death, they found it loaded with beta-amyloid and tau, two proteins that accumulate in the brains of people with Alzheimer’s disease.

However, he also had something in his favor. Genetic analysis revealed the man had a rare change in a gene that codes for a protein called reelin, which helps nerve cells communicate.

“In this case, it was very clear that this variant of reelin makes reelin more effective,” said Dr. Joseph Arboleda-Velasquez, associate professor of ophthalmology at Harvard University and lead author of a new study on the man.

“It gives us huge insight,” he said. “It’s very obvious that just putting more reeline in the brain can actually help patients.”

THE study has been published Monday in the journal Nature Medicine.

The enhanced reelin protein appeared to protect a very specific part of the human brain, an area behind the nose at the base of the brain called the entorhinal cortex.

“Another big idea from this case is that it looks like you might not need this all over the brain,” Arboleda-Velasquez said.

The entorhinal cortex is particularly sensitive to aging and Alzheimer’s. It is an area of ​​the brain that also sends and receives signals related to smell. Loss of smell is often a warning sign of brain changes that lead to difficulty with memory and thinking.

“So when people have Alzheimer’s disease, it starts in the entorhinal cortex and then it spreads,” Arboleda-Velasquez said.

This is the second time Arboleda-Velasquez and the team studying this extended family have found someone who has defied their genetic odds.

In 2019, scientists reported the case of a woman who should have developed Alzheimer’s disease at an early stage, but instead retained her memory and thinking skills well into her 70s.

She carried two copies of a change in her APOE3 gene which has been dubbed the Christchurch mutation. It seems to have decreased the activity of the APOE3 protein. Like reelin, APOE is a signaling molecule known to play a role in shaping a person’s risk of Alzheimer’s disease.

And it turns out that there is a connection between these two cases: the cells’ receptors for reelin are the same receptors for APOE.

“So these two patients are pointing with like big arrows. They tell us: ‘Hey, this is the way’. This is the pathway that is important for extreme protection against Alzheimer’s disease,” Arboleda-Velasquez said.

But the lane may not be as protective for everyone. The sister of the man in the new study also shared the rare protective gene change, and it helped her, but not as much. According to her family, she began to experience cognitive decline at age 58.

Arboleda-Velasquez said this could be because in women the gene’s activity seems to decrease with age, so it doesn’t produce as much reeline protein. “They may have the variant, but they don’t express it as much as men do,” he said.

The Harvard team says it is already working to develop a therapy based on these findings.

Dr. Richard Isaacson, a preventive neurologist at Florida Atlantic University, says studies like this show us something important: “In some cases, we can win a tussle against our genes.

Does that mean a cure is around the corner? That remains to be seen.

“Can we use a study like this to transform care and improve care? I hope so. I wouldn’t say we’re there yet,” said Isaacson, who was not involved in this research. “But I think it’s an important study.”