Researchers have identified a man with a rare genetic mutation that prevented him from developing dementia at an early age. The survey results were published on May 15. natural medicinecould help researchers better understand the causes of Alzheimer’s disease and lead to new treatments.
Francisco Lopera, a neurologist at the University of Antioquia in Medellín, Colombia, has spent nearly 40 years observing large families who develop Alzheimer’s disease in their 40s or earlier. Many of the approximately 6,000 families carry a genetic mutation called a Paisa mutation that inevitably leads to early-onset dementia. Now, however, Lopera and his colleagues have identified a family with a second gene mutation. The mutation protected him from dementia until he was 67.
“That paper made the hairs on my arms stand on end,” says neuroscientist Katherine Kazorovsky of the University of Michigan in Ann Arbor. “This is a very important new avenue for the pursuit of new treatments for Alzheimer’s disease.”
mutant protein
Lopera and colleagues analyzed the genomes and medical histories of 1,200 Colombians with dementia-causing paisa mutations around the age of 45 to 50. They identified this man as having the second mutation when he was 67 years old and had only mild cognitive impairment.
When researchers scanned his brain, they found high levels of sticky protein complexes known as amyloid plaques, thought to kill neurons and cause dementia, and accumulate as the disease progresses. A protein called tau was also discovered. Study co-author Joseph Arboleda, an ophthalmologist at Harvard Medical School in Boston, said the brain resembled someone with severe dementia. However, one small brain region called the entorhinal cortex, which coordinates skills such as memory and navigation, had lower levels of tau.
Researchers found that the man had a mutation in a gene that encodes a protein called Reelin, which has been linked to brain disorders such as schizophrenia and autism. Little is known about Reelin’s role in Alzheimer’s disease, so researchers genetically engineered mice with the same mutation. In mice, mutant forms of Reelin chemically modified the tau protein, limiting its ability to cluster around neurons.
This study challenges the theory that Alzheimer’s disease is primarily caused by amyloid plaques, which are the target of several drugs recently approved by the US Food and Drug Administration. These drugs effectively clear amyloid from the brain, but only moderately improve the rate of cognitive decline.
Yadong Huang, a neurologist at the Gladstone Institute in San Francisco, Calif., said the fact that the man had been mentally healthy for so long despite having large numbers of amyloid plaques in his brain was not surprising. It suggests that Alzheimer’s disease is more complex. He suggests that Alzheimer’s disease may have multiple subtypes, only some of which can be caused by amyloid. “It takes different pathways to truly and ultimately deal with this disease,” he says. The link to tau is particularly promising, he said, as it suggests that tau is involved in declining mental function. Several therapies that target tau are currently in clinical trials.
sharing mechanism
Lopera said the Reelin mutation is extremely rare in the general population, but his team is now looking for this and other mutations among people with the Paisa mutation. This man’s sister had both the Paisa and Reelin mutations, but at age 58 she developed cognitive impairment and at age 64 she developed severe dementia. This was slower than the average for people with the Paisa mutation. The authors say she had experienced a head injury and had other disorders that may have contributed to her developing dementia earlier than her brother.
Dr. Arboleda points out that the mutated Reelin protein binds to the same receptor as a protein called APOE, which is also associated with Alzheimer’s disease in people without the Paisa mutation. In 2019, the same group identified women with Paisa mutations who developed dementia 30 years later than average due to APOE mutations. Like the men in the latest study, the women’s brains contained much higher levels of amyloid than expected in people with few symptoms of Alzheimer’s disease.
“This is really cool because it shows that there are some common mechanisms,” says Kasorovski. Reelin and APOE compete for binding to their receptors, and the two findings suggest that either the stronger Reelin protein or the weaker APOE protein can protect the brain from disease. Dr. Arboleda said this is even more true in cases of sporadic Alzheimer’s disease, where Reelin or APOE-targeted therapies tend to be less aggressive and slower to progress than the early-onset form experienced by Colombian families. It suggests that it may be effective.
Like many Alzheimer’s patients, the man’s hippocampus (the region of the brain responsible for learning and memory) was smaller than average at the time of death, suggesting advanced degeneration. But his cognitive abilities remained relatively intact, Kasorovski said, so neurons in other parts of the brain could have been repurposed to compensate for the damage. Knowing whether such a thing occurs could help future treatment strategies, she added.
“Most of the research has focused on why some people get Alzheimer’s disease, and very little of it is in the context of the disease’s counteracting factors,” Huang said. More research is needed to elucidate the mechanisms by which Reelin and APOE affect tau and whether targeting these proteins can help Alzheimer’s patients without Paisa mutations, he said. It states that “This is one of the few cases that actually opens the door for anti-Alzheimer’s disease research.”
This article is reprinted with permission and was first published May 15, 2023.
