Bengaluru: An international group of scientists has discovered an extremely rare genetic mutation that makes a person resistant to Alzheimer’s disease — only the second such case of resilience to be identified so far.
In their study, published in the journal Nature Medicine Monday, a team of researchers from Colombia, Germany, and the US have cited the case of a 67-year-old man whose cognition remained intact despite all the markers of a form of genetically inherited Alzheimer’s in his brain.
The findings, published Monday, highlight a novel molecular pathway that could be targeted by therapeutics to increase resilience to Alzheimer’s.
In the study, researchers analysed data collected from 1,200 participants in Colombia with PSEN1 — a genetic mutation that leads to a form of Alzheimer’s called autosomal dominant Alzheimer’s disease (ADAD), making those with the gene predisposed to it.
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What researchers found
ADAD is a form of Alzheimer’s that develops before the age of 65. Those predisposed to it generally see an onset between the ages 30 and 60, leading to an early death.
The research team wanted to understand the disease’s progressive effects on cognition on people with the PSEN1 genetic mutation.
While studying the data, the team identified a man who was “cognitively intact” at 67, despite carrying the mutation for early-onset ADAD. Researchers said that the individual had a mutation called COLBOS in the RELN gene.
This gene provides instructions for making a protein called reelin. Produced in the brain both before and after birth, the protein is released by certain brain cells and binds to specific receptor proteins.
According to researchers, the COLBOS mutation appears to prevent the excess accumulation of a protein called tau in neurons or signal-carrying nerve cells in the brain.
Tau accumulation is known to facilitate the onset of Alzheimer’s.
Researchers immediately recognised this as being similar to that of a previously identified case of delayed ADAD in a Colombian woman.
It was confirmed in 2019 that the “cognitively intact” woman was in her late 70s but had the genetic profile of someone who should have had Alzheimer’s by 40.
In that case, the same team had identified another rare mutation called Christchurch in APOE, a gene that provides instructions for making a protein called apolipoprotein E, which in turn combines with fats to make lipoproteins.
Christchurch, the researchers had said then, had prevented the binding of glucose to another specific gene, protecting the individual from Alzheimer’s and other forms of dementia.
In both cases, the individuals displayed different but related genetic mutations that resisted dementia, especially ADAD.
The most recent discovery, authors say in their findings, highlight an entirely new molecular pathway that confers resistance and resilience to neurodegeneration and cognitive impairment driven by Alzheimer’s and dementia in general.
Colombia’s contribution to Alzheimer’s research
Colombia makes a very unique contribution to Alzheimer’s research — according to the Alzheimer Research Forum, a website that curates information on the disease, an entire community in the Andes that has been cut off historically from the rest of the nation has a genetic mutation for Alzheimer’s.
This community, which consists of several families scattered across many villages in the Andes mountains and going back nearly seven generations to the early 1700s, has contributed to Alzheimer’s research for decades.
Of the 5,000 or so living members, nearly 1,000 are estimated to carry the mutation PSEN1, with 400 confirmed carriers. The presence of this mutation causes progressive cognitive impairments such as loss in memory or loss of verbal fluency, starting at age 45 on average.
The disease progresses rapidly, resulting in dementia by age 50 and then death in the 60s.
The same Colombian, American and German team that has authored this study and had discovered the other resilience gene has been conducting studies here for decades in an attempt to understand how the disease progresses.
(Edited by Uttara Ramaswamy)
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