Researchers at Columbia University have discovered a genetic variant that reduces the likelihood of developing Alzheimer’s disease by up to 70%, potentially protecting countless people from the disease. The discovery of the protective variant, which appears to allow toxic forms of amyloid out of the brain and through the blood-brain barrier, supports emerging evidence that the brain’s blood vessels play a significant role in Alzheimer’s disease and could herald a new direction in therapeutic development.
Therapy Targeting Fibronectin Could Counteract Alzheimer’s Disease
Alzheimer’s disease begins with amyloid deposits in the brain, but the disease manifestations are the result of changes that occur after the deposits appear. The new findings suggest that some of these changes occur in the brain’s blood vessels and that researchers may be able to develop new types of therapies that mimic the gene’s protective effect to prevent or treat the disease.
The protective variant identified in the study occurs in a gene that makes fibronectin, a component of the blood-brain barrier, a lining that surrounds the brain’s blood vessels and controls the movement of substances in and out of the brain. Fibronectin is normally present in the blood-brain barrier in very small amounts, but it is elevated 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 the accumulation of excess fibronectin at the blood-brain barrier.
This gave the researchers the idea that excess fibronectin could prevent the breakdown of amyloid deposits in the brain. The researchers confirmed this hypothesis in a zebrafish model of Alzheimer’s disease and have further studies in mice in progress. They also found that reducing fibronectin in the animals increased amyloid clearance (clearing or detoxification capacity of the brain) and improved other damage caused by Alzheimer’s disease. These results gave them the idea that a therapy targeting fibronectin and mimicking the protective variant could provide strong protection against the disease in humans.
The latest treatments for Alzheimer’s disease target the amyloid deposits directly and are very effective at clearing the deposits through the immune system. However, removing the deposits in this way does not improve symptoms or repair other damage. According to the researchers, it may be necessary to start removing amyloid much earlier, and they believe that this can be done via the bloodstream.
Genetic Variants As a Protective Factor
The researchers discovered the protective variant in people who never developed symptoms but had inherited the e4 form of the APOE gene, which significantly increases the risk of developing Alzheimer’s disease. They hypothesized that these resistant people might have genetic variants that protect them from APOEe4. To find protective mutations, the Columbia researchers sequenced the genomes of several hundred APOEe4 carriers over the age of 70 from different ethnic backgrounds, including those with and without Alzheimer’s disease. The study identified the fibronectin variant, and the Columbia team published its findings in a preliminary paper that was made available to other researchers. Based on the Columbia team’s observations, another group from Stanford and Washington Universities repeated the study in an independent cohort of APOEe4 carriers who were predominantly of European descent. They found the same fibronectin variant. Combining the data from their 11,000 participants, the two groups were able to calculate that the mutation reduces the likelihood of developing Alzheimer’s disease by 71% in APOE4 carriers and delays the disease by about four years in those who eventually develop it. The researchers estimate that 1 to 3% of APOEe4 carriers in the United States – about 200,000 to 620,000 people – may also carry the protective fibronectin mutation.
Although the fibronectin variant was discovered in APOEe4 carriers, it could also protect people with other forms of APOE from Alzheimer’s disease. According to the researchers, there is a significant difference in fibronectin levels in the blood-brain barrier between cognitively healthy people and those with Alzheimer’s disease, regardless of their APOEe4 status. Anything that reduces excess fibronectin should offer some protection, and a drug capable of doing so could be a significant step forward in the fight against this debilitating disease.