It works by preventing build-up of fibronectin, a component of the blood-brain barrier that controls the movement of substances in and out of the brain
A senior citizen. Alzheimer’s mostly affects the elderly. Photo from iStock for representation Researchers seem to have worked out why some people are protected from Alzheimer’s disease despite carrying a high risk gene linked to the debilitating condition. This new finding could potentially open up treatment options that mimic the gene’s protective effect.
Carrying out this protective function is a mutated version of a gene that makes fibronectin — a component of the blood-brain barrier (BBB), which is a lining surrounding the brain’s blood vessels involved in controlling the movement of substances in and out of the brain, according to a new study.
This gene variant appears to reduce the chances of developing Alzheimer’s disease by 71 per cent, highlighted the study published in Acta Neuropathologica.
Previous studies have identified that a gene variant called APOEε4 to be a major genetic risk factor for Alzheimer’s disease.
However, some healthy individuals also possess APOEε4, suggesting certain mechanisms could be at play in the brain, cancelling out its pathological effects.
“These resilient people can tell us a lot about the disease and what genetic and non-genetic factors might provide protection,” Badri N Vardarajan, assistant professor of neurological science at Columbia University and one of the authors, said in a statement.
“We hypothesised that these resilient people may have genetic variants that protect them from APOEε4,” he added.
To gain insights into this, Vardarajan and his colleagues sequenced the genomes of several hundred people — with and without Alzheimer’s disease — over 70 carrying the APOEε4 variant. They belonged to various ethnic backgrounds.
Their analysis highlighted the role of variant of fibronectin. Further, another group from Stanford and Washington universities replicated the study with participants who were largely of European origin. They also arrived at the same results.
The two groups then combined their data from 11,000 participants and found that the newly discovered fibronectin mutation reduces the odds of developing Alzheimer’s among those carrying APOEε4 variant gene by 71 per cent. It also delays the development of the disease by roughly four years among those who end up developing the disease later.
Roughly 1-3 per cent of APOEε4 carriers in the United States—roughly 200,000 to 620,000 people—may also carry the protective fibronectin mutation, the researchers estimated.
The team also conducted experiments on zebrafish — organisms that possess a backbone like humans, making them ideal for studies of the body’s organisation and function.
When fibronectin was reduced, the team observed an increase in clearance of amyloid and an improvement in other damage caused by Alzheimer’s disease. A build-up of amyloid beta protein in the brain is thought to cause Alzheimer’s disease.
“We hypothesise that by preventing building of fibronectin, the integrity of BBB is maintained and the clearance of amyloid from the brain is not hampered,” Vardarajan told Down To Earth.
When the BBB is compromised, he added, toxic molecules, pathogens, and inflammatory mediators may infiltrate the brain more easily, leading to neuronal damage and inflammation and accelerating the neurodegenerative process characteristic of Alzheimer’s.
In healthy individuals, the BBB helps regulate the transport of amyloid beta into and out of the brain. However, dysfunction of the BBB can disrupt this balance, leading to the accumulation of amyloid beta in the brain, the expert explained.
Though the team detected this fibronectin variant in people possessing APOEε4, they think it could also protect people with other forms of the APOE gene as well
“Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition,” Caghan Kizil, co-leader of the study explained.
The study was conducted in Caribbean Hispanics, non-Hispanic Whites and African Americans. Vardarajan believes that the fibronectin variant could be important in other populations like (east) Asian and south Asian as well. “But it is possible that they might harbour different variants in the same gene,” he explained.
So far, the United States Food and Drug Administration (FDA) has approved three drugs to treat the symptoms caused by mild to moderate Alzheimer’s disease. These medications are designed to delay decline in memory and do not prevent the disease from getting worse over time.
The regulator has also granted accelerated approval for two drugs that may slow the progression of mild Alzheimer’s disease.
These options, according to Vardarajan, work in the later stage of the course of the disease. It would be more helpful to find potential targets of early intervention by identifying resilient factors to Alzheimer’s disease in high risk individuals, he added.
For those with moderate to severe disease, the FDA has approved a drug to treat the symptoms, according to Stanford Medicine.
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