(CTN News) – The mutation protected man from dementia at a young age. This discovery could lead to new treatments for Alzheimer’s, according to a Nature Medicine1 study.
During his nearly 40 years at the University of Antioquia in Medellin, Colombia, neurosurgeon Francisco Lopera has followed a family of Alzheimer’s patients.
Approximately 6,000 members of this family carry the paisa mutation, which inevitably causes early-onset dementia.
He and his collaborators have discovered a family member with a second genetic mutation that protected him from dementia until he was 67 years old.
“Reading that paper made my hair stand up,” says Catherine Kaczorowski, a neuroscience researcher at the University of Michigan. “It offers a great opportunity for developing new Alzheimer’s therapies.”
Proteins with mutations
The genomes and medical histories of 1,200 Colombians with the paisa mutation, which causes dementia between 45 and 50, were examined by Lopera and his colleagues. At the age of 67, the man with the second mutation was diagnosed with mild cognitive impairment.
Researchers found high levels of sticky protein plaques called amyloid plaques in his brain, which kill neurons and cause dementia, along with tau protein that accumulates with the disease.
A Harvard Medical School ophthalmologist, Joseph Arboleda, reported that the brain looked like that of a person with severe dementia. Memory and navigation skills are coordinated by the entorhinal cortex, a small brain region with low tau levels.
He had a mutation in a gene that codes for reelin, a protein associated with brain disorders such as schizophrenia and autism.
As reelin’s role in Alzheimer’s is unknown, researchers genetically engineered mice with the same mutation. As a result of the mutation, mice’s tau protein was chemically modified, making it less able to cluster around neurons.
A new study challenges the theory that Alzheimer’s disease is mainly caused by amyloid plaques, the target of several FDA-approved drugs. Amyloid is effectively removed from the brain using these drugs, but cognitive decline rates only moderately improve.
Mechanisms shared by both
Among people with paisa mutations, Lopera’s team is now trying to identify this mutation and others.
Despite having both the reelin and paisa mutations, the man’s sister developed cognitive impairment at age 58 and severe dementia at 64 – later than the average person with the paisa mutation. She may have developed dementia earlier than her brother due to head injuries and other disorders.
As Arboleda notes, the mutated reelin protein binds to the same receptors as APOE, which is also associated with Alzheimer’s disease in people without the paisa mutation.
Due to a mutation in APOE2, a woman with the paisa mutation developed dementia 30 years later than average.
This woman’s brain also contained much higher levels of amyloid than would be expected in someone with so few symptoms of Alzheimer’s.
A large portion of Alzheimer’s research is devoted to explaining why some people get the disease, but only a small percentage is devoted to conditions that can prevent it, according to Huang.
Identifying the mechanism by which reelin and APOE affect tau, as well as targeting these proteins, would be helpful to people without the paisa mutation. A case like this opens the door for anti-Alzheimer’s research.
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