rs140926439 Variant in the Fibronectin FN1 Gene Lowers Risk of Alzheimer Disease in APOEε4 Carriers in the UK Biobank Cohort

Background: A genetic variant in the fibronectin FN1 gene reduces the odds of developing AD by up to 70%. This variant, rs140926439, appears to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer disease (AD), but the variant appears to counteract its effects. Our study aims to replicate findings from previous research that identified a relationship between the fibronectin FN1 gene variant rs140926439 and a lower risk of Alzheimer disease (AD) in APOEε4 carriers. Methods: We analyzed the relationship of FN1 SNP rs140926439, APOEε4, and AD in the UK Biobank cohort. Results: When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD, while 0.43% of APOEε4 carriers or homozygotes had AD. This difference was significant ( P <0.001, 2-tail the Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD, while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant ( P =1). To examine the overall relationship of rs140926439 and APOE isoform to AD, we used the univariate general linear model, AD (present or absent) dependent variable, rs140926439 (present or absent) and APOE isoform (APOEε2/3 or APOEε4 carrier or homozygote) as fixed factors. The effect of rs140926439 was significant ( P =0.025). The effect of the APOE isoform was significant ( P =0.030). There was also a significant interaction between rs140926439 and APOE isoform ( P =0.031). Conclusion: Fibronectin is an adhesive molecule that is essential to wound healing, especially to the production of the extracellular matrix and reepithelialization. Some cases of AD may be due to the initiation of the brain wound healing process, often in the absence of any actual wound. NSAIDS may reduce the risk of AD because they potently inhibit wound healing. FN1 appears to be a key player in AD, and its risk-lowering variant could offer insights into potential therapeutic targets. However, further research is needed to fully understand the intricate mechanisms underlying AD and to develop effective treatments.