Researchers have identified a Colombian man carrying a never-before-seen genetic mutation that protected him from the symptoms of a rare, inherited form of Alzheimer’s, characterized by a very early onset of cognitive decline, for 20 years. The discovery could lead to therapies that boost people’s resilience against the debilitating disease.
Autosomal dominant Alzheimer’s disease (ADAD) is a form of dementia caused by rare, inherited genetic mutations. In autosomal dominant inheritance – one of the ways a genetic trait can be inherited – a genetic condition occurs when a variant is present in only one allele (copy) of a particular gene.
The factors determining the development of Alzheimer’s disease are the presence of mutations in one of three genes – amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) – or duplication of the APP gene. ADAD is most commonly caused by mutations in the PSEN1 gene and is characterized by the early onset of cognitive impairment, at around 40 to 50.
Now, researchers from the University of Antioquia have reported on a Colombian man who did not develop Alzheimer’s symptoms for 20 years, despite having the genetic mutation associated with ADAD.
In the course of analyzing clinical and genetic data from 1,200 Colombian people with the PSEN1 mutation, and therefore predisposed to ADAD, the researchers discovered a man who had remained cognitively intact until the age of 67 despite carrying the mutation. He started exhibiting difficulties with short-term memory and language at 70 and, at 73, required assistance with basic activities of daily living.
They compared this man with a woman with ADAD who had previously been reported as having a mutation on a different gene, apolipoprotein E (APOE). She’d remained cognitively intact for almost 30 years after the expected age of onset of the disease.
Both she and the Colombian man showed widespread, considerable amyloid beta plaques in the brain. However, there were limited tau tangles in a region of the brain (the entorhinal cortex) characteristically affected in the early stages of the disease. Tau tangles occur when tau proteins cling to one another inside neurons. Amyloid beta plaques and tau tangles are the hallmarks of Alzheimer’s disease.
When the researchers conducted genetic sequencing on the man, they found he did not have the APOE mutation. Instead, he possessed a new type of mutation of the RELN gene. The researchers named the mutation RELN-COLBOS because the man was enrolled in the Colombia-Boston biomarker research study (COLBOS).
The RELN gene provides instructions for making a protein called reelin. In the developing brain, reelin turns on a signaling pathway that triggers neurons to migrate to their proper locations. After birth, it’s thought to play a role in neuroplasticity.
Interestingly, the man’s sister was also found to have the RELN-COLBOS mutation and, like him, also presented with delayed onset of cognitive decline, although it was not as pronounced as her brother’s.
The researchers hypothesize that reelin may be effective at limiting the production of tau tangles, but further research is required before this previously unknown molecular pathway might be exploited to develop therapies that strengthen the cognitive resilience of people at risk of Alzheimer’s disease.
The study was published in the journal Nature Medicine.
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