Alzheimer’s disease is the most common form of dementia and affects millions of people worldwide. This disease affects brain parts that control memory, thoughts, and language. Most commonly, people with Alzheimer’s disease begin to show symptoms in their mid-60s. Scientists have shown some rare cases of Alzheimer’s disease are caused by a genetic mutation known as PSEN1-E280A, which causes people to develop Alzheimer’s as early as their mid-40s, a condition called early-onset Alzheimer’s.
Scientists identified a man in Colombia who has the gene for early-onset Alzheimer’s along with a second genetic mutation called the RELN-COLBOS mutation. This man maintained a fully functional brain for around 30 years longer than the average person with early-onset Alzheimer’s. Scientists hypothesized his gene mutation could help develop treatments for others to resist Alzheimer’s. However, they needed additional case studies to test whether the genetic mutation was the sole reason for the man’s resistance to the disease.
Researchers from Colombia recently set out to study the patient with the RELN-COLBOS mutation to see how it helped him resist early-onset Alzheimer’s. They enrolled the patient in an international collaboration between the Universidad de Antioquia, Colombia, and Massachusetts General Hospital, Boston, called the Colombia–Boston biomarker research study program. This program includes more than 6000 participants, both with and without genes known to cause Alzheimer’s.
The researchers compared the Colombian man with the RELN-COLBOS mutation to early-onset Alzheimer’s patients without this mutation to see if they developed the disease in different ways. They compared each patient’s cognitive decline in terms of their motor functions, how many neurons were firing in their brains, and at what signal intensity. They also measured proteins in each patient’s brain known to help with memory and learning, like Dab1 and Tau proteins.
The researchers also collected brain tissue from the man. They performed a type of genetic profiling called single-cell RNA sequencing on his brain tissue to confirm he carried the PSEN1-E280A gene that causes early-onset Alzheimer’s. They used this same method to identify which RELN mutation he carried.
They explained that the RELN gene typically tells the body how to produce a reelin protein that controls brain development. This man had a mutation in his RELN gene that codes for an amino acid different from what it’s supposed to. Researchers have observed a similar mutation in people with other brain-related disorders like schizophrenia, bipolar disease, and autism. They named it the RELN-COLBOS mutation after the research program.
Next, the researchers looked at the man’s brain using several medical imaging methods, like positron emission tomography, or PET scans, and magnetic resonance imaging, or MRI scans. They examined these images of the man’s brain for signs of disease or other abnormalities.
They found the man’s brain contained high amounts of amyloid beta protein. They explained this protein causes people who have Alzheimer’s disease to lose their neurons and neural connections. However, they found the man’s brain also had lower than usual levels of other proteins normally associated with Alzheimer’s disease, called Tau proteins. They explained people with Alzheimer’s usually have high amounts of Tau proteins, which cause the internal skeleton of their neurons to fall apart and slows down their ability to think and remember. The researchers suggested the low levels of Tau proteins in the man’s brain were part of his resistance to Alzheimer’s.
Based on how the RELN-COLBOS mutation worked in this man, the scientists hypothesized it was a gain-of-function (GOF) mutation. A GOF mutation happens when the mutated gene gains a new function, meaning it works differently than it should. For example, a coffee machine’s function is to make coffee, but if it had a GOF mutation, it might start making orange juice instead. They classified the RELN-COLBOS mutation as a GOF mutation because the RELN gene’s normal function is to make the reelin protein, but in its mutated form, it slows down Tau protein production instead.
The researchers concluded the RELN-COLBOS mutation’s new function helped this gene regulate neural circuits damaged by Alzheimer’s disease and other types of dementia. However, they cautioned the effects of this mutation on these diseases were mild since it delayed cognitive impairment but did not stop it. They suggested future workers should study other patients with the same mutation since there are currently only a handful of cases available, and different genetic variants could also be delaying Alzheimer’s symptoms in the same patients.
