Recent study identifies genetic variant which may protect against APOE ε4

20/05/2024

People carrying the ε4-allele of the Apolipoprotein E gene (APOE ε4) have a significantly higher risk for developing Alzheimer's disease, as compared to non-carriers. However, some carriers remain cognitively healthy, indicating the presence of protective mechanisms against its pathological effects. In a recent study published in Acta Neuropathologica, a group of researchers lead by Columbia University New York (US) set out to assess genetic variants which may affect APOE ε4 in Alzheimer's disease. For this, they conducted whole genome sequencing (a method in which information about an individual’s entire genome is being collected) in a large group of people from the US. Doing so, they were specifically interested in those genetic variations only present in cognitively healthy APOE ε4 carriers. Of 510 such variants, two genes (fibronectin 1/FN1 and collagen type VI alpha 2 chain/COL6A2) were especially highly represented. FN1 encodes a protein bearing the same name, which supports cell functioning and is also found in the blood-brain barrier. 

In a second analysis step using another group of APOE ε4 carriers, the researchers found that carriership of a certain variant of FN1 (rs140926439) was associated with 71% lower odds of developing Alzheimer's disease and a later disease onset by 3.37 years, on average. In further analyses using zebrafish models, deletion of an equivalent to the FN1 gene gave rise to beneficial neuronal processes, such as less gliosis (change in glial cells in reaction to disease or injury to the central nervous system). While fibronectin generally supports functioning of cells, too much of it could impair the clearance of toxic proteins, and thus add to the pathogenic effect of APOE ε4. A variation in the FN1-gene, resulting in less FN1 deposition may, in turn, be protective against such pathogenic processes. The full open-access article can be read here: 

https://link.springer.com/article/10.1007/s00401-024-02721-1