Researchers working to unlock the secrets of Alzheimer’s disease say they have been given a key clue that could help protect people at risk for this type of dementia.
A man who seems destined to develop memory loss in his 40s or 50s, based on family history, maintains normal function for decades longer than he should. Apparently he was protected by a rare gene mutation that enhanced the function of a protein that helps nerve cells communicate.
Scientists say that understanding how this gene change protected his brain could help prevent Alzheimer’s in other people.
The man was part of a large family in Antioquia, Colombia, with many members who inherited a mutated gene called presenilin-1, or PSEN1. PSEN1 carriers are almost certain to develop Alzheimer’s disease at a relatively young age.
The man, who had the PSEN1 mutation, had problems with memory and thinking. He was diagnosed with mild dementia at age 72, then experienced further memory loss and an infection. He died of pneumonia at the age of 74.
But by all indications, he should have developed memory and thinking problems decades ago. When doctors examined his brain after death, they found it full of beta amyloid and tau, two proteins that accumulate in the brains of people with Alzheimer’s.
However, he also has something going in his favor. A genetic analysis revealed that the man had a rare mutation in a gene that codes for a protein called reelin, which helps nerve cells communicate.
“In this case, it’s very clear that this reelin variant makes reelin more efficient,” said Dr. Joseph Arboleda-Velasquez, an associate professor of ophthalmology at Harvard University and lead author of a new study on men.
“That gives us a big perspective,” he said. “It’s very clear that just putting more reelin in the brain can help patients.”
The study was published Monday in the journal Nature Medicine.
The enhanced reelin protein seems to protect a specific part of the male brain, an area behind the nose at the base of the brain called the entorhinal cortex.
“Another big insight from this case is, apparently you don’t need it everywhere in the brain,” Arboleda-Velasquez said.
The entorhinal cortex is particularly sensitive to aging and Alzheimer’s. It is a part of the brain that also sends and receives signals related to smell. Loss of smell is often a harbinger of brain changes that lead to memory and cognitive 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, scientists the case is reported of a woman who should have developed early-onset Alzheimer’s but instead retained her memory and cognitive abilities well into her 70s.
He carried two copies of a change in his APOE3 gene called the Christchurch mutation. APOE3 protein activity seems to be reduced. Like reelin, APOE is a signaling molecule 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 the cells for reelin are the same receptors for APOE.
“So these two patients are pointing like big arrows. They tell us, ‘Hey, this is the path. This is the pathway that is important for acute protection against Alzheimer’s,’ ” Arboleda-Velasquez said.
But the path may not be as protective for everyone. The sister of the man in the new study also shared the rare protective gene mutation, and it helped her, but not much. According to his family, he began experiencing cognitive decline at the age of 58.
Arboleda-Velasquez said that may be because in women, the gene’s activity seems to decrease with age, so it doesn’t make as much reelin protein. “They may have the variant, but they don’t express it like men,” she said.
The Harvard team says they are now working to develop a therapy based on these findings.
Dr. Richard Isaacson, a preventive neurologist at Florida Atlantic University, says that studies like this show us something important: “In some cases, we can win a tug of war against our genes.”
Does this mean a cure is near? It remains to be seen.
“Can we use a study like this to change 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 I think this is an important study.”