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 from this form of dementia.
A person who appears destined to develop memory loss in his 40s or 50s, based on family history, has maintained normal function for decades. He appears to have been protected by a rare genetic mutation that improved the function of a protein that helps nerve cells communicate.
Scientists say understanding how this genetic change protected his brain could help prevent Alzheimer’s disease in others.
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.
A man with a PSEN1 mutation eventually developed memory and thinking problems. He was diagnosed with mild dementia at age 72 and later experienced severe memory loss and infections. He died of pneumonia at the age of 74.
But by all indications, he should have had memory and thinking problems decades ago. When doctors examined his brain after death, they found it rich in beta-amyloid and tau, two proteins that accumulate in the brains of people with Alzheimer’s disease.
However, something worked in his favor. Genetic analysis revealed that humans have a rare mutation in a gene that encodes a protein called reelin that helps nerve cells communicate.
“In this case, it was very clear that this variant of reelin makes reelin work better,” said Dr. Joseph Arbolida-Velasquez, associate professor of ophthalmology at Harvard University and lead author of the new human study.
“It gives us a great deal of insight,” he said. “This makes it very clear that putting more Reelin in the brain can actually help patients.”
The The study was published Monday in the journal Nature Medicine.
The enhanced reelin protein appeared to protect a specific area of the human brain, an area at the base of the brain that sits behind the nose called the entorhinal cortex.
“Another big insight from this case is that you don’t seem to need it everywhere in the brain,” Arbolida-Velasquez said.
is the entorhinal cortex Elderly people are especially sensitive and for Alzheimer’s disease. This is the part of the brain that sends and receives signals related to the sense of smell. Loss of smell is often a precursor to brain changes that lead to memory and thinking problems.
“So when people have Alzheimer’s, it starts in the entorhinal cortex and then it spreads,” Arbolida-Velasquez said.
This is the second time Arboleda-Velasquez and the team studying this extended family have found someone who has overcome their genetic odds.
In 2019, scientists He announced the case A woman who should have developed early-onset Alzheimer’s disease but instead maintained her memory and thinking skills into her 70s.
He carried two copies of a mutation in his APOE3 gene, nicknamed the Christchurch mutation. It appears to decrease the activity of the APOE3 protein. Like reelin, APOE is a signaling molecule that plays a role in shaping a person’s risk for Alzheimer’s disease.
It turns out that there is a link between these two phenomena: the receptors on cells for reelin are the same receptors for APOE.
“So these two patients are pointing like big arrows. They’re telling us, ‘Hey, this is the pathway. This is the critical pathway for serious protection against Alzheimer’s disease,'” Arbolida-Velasquez said.
But the path is not safe for everyone. The sister of the man in the new study also shared a rare protective genetic mutation that helped her, but not as much. According to his family, he began experiencing cognitive decline at the age of 58.
Arboleda-Velasquez says that in women, the gene’s activity seems to decrease with age, so it doesn’t make as much reelin protein. “They may have variation, but they don’t express it as much as men,” she said.
The Harvard team says they are already working to develop a treatment based on these findings.
Preventive neurologist at Florida Atlantic University, Dr. Richard Isaacson, studies like this show us something important: “In some cases, we can win a tug against our genes.”
Does that mean a cure is around the corner? That should 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 the research. “But I think it’s an important study.”