Man may hold a clue to preventing Alzheimer’s, scientists say. Here’s what to know.

A man who seemed fated to develop memory loss in his 40s or 50s, based on family history, kept normal function for decades longer than he should have. He seems to have been protected by a rare gene change that enhanced the function of a protein that helps nerve cells communicate.

Scientists say that understanding how this gene change defended his brain may help prevent Alzheimer’s in other people.

The man is part of a large family in Antioquia, Colombia, with many members who 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, did eventually develop memory and thinking problems. He was diagnosed with mild dementia at the age of 72, then experienced more 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 death, they found it loaded with beta amyloid and tau, two proteins that accumulate in the brains of people with Alzheimer’s.

However, he had something working in his favor, too. A genetic analysis revealed that 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 reelin variant makes reelin work better,” said Dr. Joseph Arboleda-Velasquez, an associate professor of ophthalmology at Harvard University and lead author of a new study on the man.

“That gives us a huge insight,” he said. “It makes it very obvious that just putting more reelin in the brain may actually help patients.”

The study was published Monday in the journal Nature Medicine.

The enhanced reelin protein seemed to be protecting a very specific part of the man’s brain, an area that sits behind the nose at the base of the brain called the entorhinal cortex.

“Another big insight from this case is, it seems like maybe you don’t need this everywhere in the brain,” Arboleda-Velasquez said.

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

“So when people have Alzheimer’s, 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 defied their genetic odds.

In 2019, the scientists reported the case of a woman who should have developed early Alzheimer’s but instead maintained her memory and thinking abilities until her 70s.

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

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

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

But the pathway 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 experiencing cognitive decline at age 58.

Arboleda-Velasquez said that may be because in women, the activity of the gene seems to drop off with age, so it doesn’t make as much reelin protein. “They can have the variant, but they don’t express it as much as men,” he said.

The Harvard team says they’re already working toward 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 certain cases, we can win a tug of war against our genes.”

Does this 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 that we’re there just yet,” said Isaacson, who was not involved with this research. “But I think this is this is an important study.”