rs140926439 variant in the Fibronectin FN1 gene protects against Alzheimer’s disease in APOEε4 carriers in the UK Biobank cohort

TL;DR

A genetic variant in the FN1 gene protects against Alzheimer's disease in people who carry the APOEε4 gene variant, according to a study using UK Biobank data.

Contribution

The study identifies a protective variant in the FN1 gene that reduces Alzheimer’s risk in APOEε4 carriers and reveals a significant gene-gene interaction.

Findings

The rs140926439 variant in FN1 reduces Alzheimer’s odds by up to 70% in APOEε4 carriers.

The presence of rs140926439 eliminates the increased Alzheimer’s risk typically seen in APOEε4 carriers.

There is a significant interaction between rs140926439 and APOE isoform in influencing Alzheimer’s disease risk.

Abstract

A protective genetic variant in the fibronectin FN1 gene reduces the odds of developing AD by up to 70%. This variant, rs140926439, seems to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer’s Disease (AD), but the protective variant appears to counteract its effects.

In the current study, we analyzed the relationship of FN1 SNP rs140926439, APOEε4, and AD in the UK Biobank cohort.

When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD while 0.40% of APOEε4 carriers or homozygotes had AD. This difference was significant (p < 0.001, 2 tail 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 = 0.030). The effect of APOE isoform was significant (p = 0.034). There was also a significant interaction between rs140926439 and APOE isoform (p = 0.030).

Fibronectin is an adhesive molecule that is essential to wound healing, especially to the production of 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 risk of AD because they potently inhibit wound healing. FN1 appears to be a key player in AD, and its protective 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.

Figures