Neuroscientists have found a genetic mutation that can lower the risk of developing Alzheimer’s disease by up to 70%. This discovery could potentially protect thousands of individuals in the United States from the disease. The variant allows toxic forms of amyloid to exit the brain and pass through the blood-brain barrier, which supports the growing evidence that the brain’s blood vessels are involved in Alzheimer’s disease.Alzheimer’s disease is greatly affected by amyloid deposits in the brain, which could lead to a new approach in developing therapies. According to Caghan Kizil, PhD, who co-led the study that discovered the variant and is an associate professor at Columbia University Vagelos College of Physicians and Surgeons, “Alzheimer’s disease may start with amyloid deposits, but the actual symptoms result from changes that occur after the deposits form.” The study’s findings indicate that some of these changes take place in the brain’s vasculature, suggesting the potential for new types of therapeutic development.
Therapies that imitate the gene’s protective effect in order to prevent or treat the disease.
A promising drug target?
The protective variation discovered in the study is found in a gene responsible for producing fibronectin, a key component of the blood-brain barrier. This barrier lines the blood vessels surrounding the brain and regulates the movement of substances in and out of the brain.
Normally, fibronectin is only present in small amounts in the blood-brain barrier, but in individuals with Alzheimer’s disease, it is significantly increased. The variation identified in the fibronectin gene appears to provide protection against Alzheimer’s disease by stopping the excessive buildup of fibronectin.The excess accumulation of fibronectin at the blood-brain barrier is a concern, according to Kizil. It has led to the theory that the presence of too much fibronectin could be hindering the removal of amyloid deposits from the brain. This hypothesis has been validated in a zebrafish model of Alzheimer’s disease and is currently being further studied in mice. The researchers also observed that a reduction in fibronectin in the animals led to increased clearance of amyloid and a reduction in other damage associated with Alzheimer’s disease. These findings have led to the consideration of a therapy targeting fibronectin and replicating its effects.According to study co-leader Richard Mayeux, MD, the protective variant could offer a strong defense against the disease in people. The latest treatments for Alzheimer’s disease focus on directly targeting the amyloid deposits and are highly effective at eliminating the deposits through the immune system. However, simply removing the deposits in this manner does not improve symptoms or repair other damage. Mayeux suggests that amyloid may need to be cleared much earlier and believes this can be achieved through the bloodstream. This is why there is excitement about this approach.The identification of this variant in fibronectin may present a promising opportunity for drug development.”
Protective gene discovered in individuals resistant to Alzheimer’s disease
Scientists detected the protective variant in individuals who never showed symptoms of Alzheimer’s disease despite inheriting the e4 form of the APOE gene, which significantly elevates the risk of developing the disease.
“These resilient individuals can offer valuable insights into the disease and the potential protective factors, both genetic and non-genetic,” states Badri N. Vardarajan, PhD, co-leader of the study and assistant professor.The article discusses the work of a researcher at Columbia University who specializes in using computational methods to identify genes related to Alzheimer’s disease. The researcher and their team hypothesized that some people may have genetic variants that protect them from a specific risk factor for Alzheimer’s disease. To test this hypothesis, they sequenced the genomes of hundreds of individuals over the age of 70 who carried a specific genetic risk factor for the disease, including those with and without Alzheimer’s. Many of the participants were from Northern Manhattan and were part of an ongoing aging project at Columbia University.A study conducted by Columbia University’s Department of Neurology for over 30 years has identified the fibronectin variant. The Columbia team shared their results in a preprint for other researchers to review. Another group from Stanford and Washington universities replicated the study in an independent cohort of APOEe4 carriers, mostly of European origin, and found the same fibronectin variant. This confirmation of the finding gives the Columbia team more confidence in their result, according to Vardarajan. The two groups combined the data on their 11,000 participants.A study involving participants found that a specific mutation reduces the risk of developing Alzheimer’s in APOE4 carriers by 71% and delays the onset of the disease by approximately four years for those who do develop it.
The researchers believe that approximately 1% to 3% of APOEe4 carriers in the United States, which translates to roughly 200,000 to 620,000 individuals, may also have the protective fibronectin mutation.
Promising Potential for Treatment
Although the fibronectin variant was initially found in APOEe4 carriers, it may have the potential to protect against Alzheimer’s in individuals with other forms of APOE.
“There’s a significant difference in fibr rnrnKizil explains, “We observed differences in fibronectin levels in the blood-brain barrier between cognitively healthy individuals and those with Alzheimer’s disease, regardless of their APOEe4 status. Anything that can reduce the excess fibronectin could offer some protection, and a drug that accomplishes this could be a significant step forward in the fight against this debilitating condition.”
Journal Reference:
Prabesh Bhattarai, Tamil Iniyan Gunasekaran, Michael E. Belloy, Dolly Reyes-Dumeyer, Dörthe Jülich, Hüseyin Tayran, Elanur Yilmaz, Delaney Flaherty, Bengisu Turgutalp, Gauthaman Sukumar, Camille AlbaElisa Martinez McGrath, Daniel N. Hupalo, Dagmar Bacikova, Yann Le Guen, Rafael Lantigua, Martin Medrano, Diones Rivera, Patricia Recio, Tal Nuriel, Nilüfer Ertekin-Taner, Andrew F. Teich, Dennis W. Dickson, Scott Holley, Michael Greicius, Clifton L. Dalgard, Michael Zody, Richard Mayeux, Caghan Kizil, Badri N. Vardarajan. Researchers have discovered that rare genetic variation in fibronectin 1 (FN1) may provide protection against APOEε4 in Alzheimer’s disease. The findings were published in Acta Neuropathologica, 2024; 147 (1) DOI: 10.1007/s00401-024-02721-1 rnrn