The risk of developing Alzheimer’s disease is significantly increased in people who have the APOEε4 genetic variant. However, there are also older people who, although they have this variant, do not present symptoms of cognitive impairment, which suggests that there could be mechanisms at the cellular level that protect against the negative effects of APOEε4, although these are unknown. Now, researchers at Columbia University Irving Medical Center have discovered a genetic variant that reduces the chances of developing Alzheimer’s disease by up to 70% and that could be protecting thousands of people against this type of dementia.
The discovery of the protective variant, which appears to make it easier for toxic forms of amyloid to leave the brain and cross the blood-brain barrier, supports emerging evidence that blood vessels in the brain play an important role in Alzheimer’s disease and could help find new therapeutic options. The results of the study have been published in the journal Acta Neuropathologica.
“Alzheimer’s disease may begin with amyloid deposits in the brain, but the manifestations of the disease are the result of changes that occur after the deposits appear,” explained Caghan Kizil, co-director of the study that identified the variant and professor associate of neurological sciences at the Taub Institute and Vagelos College of Physicians and Surgeons at Columbia University. “Our findings suggest that some of these changes occur in the vasculature of the brain and that we may be able to develop new types of therapies that mimic the protective effect of the gene to prevent or treat the disease,” he adds.
The protective variant identified by the study occurs in a gene that produces fibronectin, a component of the blood-brain barrier, a lining that surrounds blood vessels in the brain and controls the movement of substances in and out of the brain. Fibronectin is usually present in the blood-brain barrier in very small amounts, but increases in large amounts in people with Alzheimer’s disease. The variant identified in the fibronectin gene appears to protect against Alzheimer’s disease by preventing excessive accumulation of fibronectin at the blood-brain barrier.
“It’s a classic case of too much of a good thing,” Kizil says. “It made us think that excess fibronectin might be preventing the removal of amyloid deposits from the brain.” The researchers confirmed that hypothesis in a zebrafish model of Alzheimer’s disease and have additional studies in mice underway. They also found that reducing fibronectin in the animals increased amyloid clearance and improved other damage caused by Alzheimer’s disease.
A promising discovery to prevent and combat Alzheimer’s
“These results gave us the idea that a therapy targeting fibronectin and mimicking the protective variant could provide a strong defense against the disease in people,” says study co-leader Dr. Richard Mayeux, professor of neurology and Gertrude H. Sergievsky Professor of Neurology, Psychiatry and Epidemiology.
New treatments for Alzheimer’s disease target amyloid deposits directly and are very efficient at removing the deposits through the immune system. However, simply removing the deposits in this way does not improve symptoms, nor repair other damage. “We may need to start clearing amyloid much earlier and we think that can be done through the bloodstream,” Mayeux adds. “That’s why we are excited about the discovery of this variant of fibronectin, which may be a good target for drug development.”
The researchers discovered the protective variant in people who never showed symptoms, but who had inherited the e4 of the APOE gene, which significantly increases the risk of developing Alzheimer’s disease. “These resistant individuals may help us better understand the disease and what genetic and nongenetic factors might provide protection,” said study co-leader Badri N. Vardarajan, assistant professor of neurological sciences (at the Gertrude H. Sergievsky Center and the Institute Taub) and an expert in using computational approaches to discover Alzheimer’s disease genes. “We think these resilient people may have genetic variants that protect them from APOEe4.”
“Our findings suggest that some of these changes occur in the vasculature of the brain and that we may be able to develop new therapies that mimic the protective effect of the gene to prevent or treat Alzheimer’s disease.”
To find protective mutations, the Columbia researchers sequenced the genomes of several hundred APOEe4 carriers over the age of 70 from various ethnic backgrounds, including those with and without Alzheimer’s disease. The study identified the fibronectin variant. Building on the Columbia team’s observations, another group from Stanford University and Washington University replicated the study in an independent cohort of APOEe4 carriers, mostly of European origin. “They found the same fibronectin variant, which confirmed our finding and gave us even more confidence in our result,” says Vardarajan.
The two groups combined data from their 11,000 participants, allowing them to calculate that the mutation reduces the odds of developing Alzheimer’s in APOE4 carriers by 71% and prevents the disease by about four years in those who eventually develop it.
Researchers estimate that 1% to 3% of APOEe4 carriers in the United States (between 200,000 and 620,000 people) may also carry the protective fibronectin mutation. The fibronectin variant, although discovered in APOEe4 carriers, may protect against Alzheimer’s disease in people with other forms of APOE.
“There is a significant difference in fibronectin levels at the blood-brain barrier between cognitively healthy individuals and those with Alzheimer’s disease, regardless of their APOEe4 status,” says Kizil. “Anything that reduces excess fibronectin should provide some protection, and a drug that does so could be an important step forward in the fight against this debilitating disease,” concludes the expert.
