The medical and Alzheimer’s communities are excited about recent discoveries revolving around correcting and understanding the gene variation most linked to the development of Alzheimer’s. It has been known for several years that the APOE4 gene variant is correlated to the development of Alzheimer’s. One copy of the APOE4 gene raises someone’s risk of developing Alzheimer’s by two to three times and having two copies makes someone 12 times more likely to develop Alzheimer’s [1].

The APOE gene provides instructions for making apolipoprotein E. This protein combines with lipids in the body to form molecules called lipoproteins. Lipoproteins package cholesterol and other fats to carry them through the bloodstream. There are at least three different variations of the APOE gene. The major ones include e2, e3, and e4. E3 is the most common allele which is found in over half of the general population [2].

Thanks to research conducted by Dr. Yadong Huang (lead investigator and professor of neurology and pathology at the University of California) and his team, we know how the APOE4 gene causes signs in human brain cells and how it is more detrimental than the APOE3 variant. An essential fact to figure out was if the APOE4 gene causes signs of dementia in the brain because it affects APOE3’s functions or because it itself has toxic effects. This fact would impact clinical care by establishing whether to increase or lower protein levels during treatment.

“If the damage is caused due to the loss of a protein’s function, you would want to increase protein levels to supplement those functions.” “But if the accumulation of a protein leads to a toxic function, you want to lower production of the protein to block its detrimental effect.” – Dr. Huang

Huang and his team of scientists discovered that the APOE4 protein has a pathogenic conformation that prevents it from functioning correctly. APOE4 increased increased production of amyloid-[beta] peptides and levels of tau phosphorylation in neurons. Their studies confirmed that it is the presence of APOE4 that causes the disease. Huang’s team realized that they could change the look and behavior of the APOE4 gene to be more like APOE3 using a previously developed small-molecule “structure corrector.” This structure corrector was able to eliminate the detrimental effects of the gene variation and is now thought to be a viable therapeutic approach to APOE4-related Alzheimer’s disease [1].

Sources:

1. Sandoiu, Ana. “Breakthrough: Researchers Fix Alzheimer’s Gene.” Medicalnewstoday, 11 Apr. 2018, www.medicalnewstoday.com/articles/321455.php   
2. “APOE Gene – Genetics Home Reference.” U.S. National Library of Medicine, National Institutes of Health, 25 Apr. 2018, ghr.nlm.nih.gov/gene/APOE.