The Mystery of APOE4
When analyzing genomic data, the identification of genetic variants involved in a disease can often precede the knowledge of how that variant actually changes any biological functions. One great example is the APOE4 variant. Although it is known to be the strongest genetic risk variant for Alzheimer’s disease, it was unknown until recently how APOE4 might contribute to Alzheimer’s.
Some evidence showed that the protein encoded by APOE4 interacts with amyloid fibrils, the proteins that make up the characteristic plaques found in Alzheimer’s brains. However, this did not fully explain why inheriting the APOE4 variant increases the risk of Alzheimer’s so dramatically: one copy of the variant increases risk by 3-fold, while two copies increase risk by 8 to 12-fold.
Altered Gene Expression in Oligodendrocytes
In a recent paper in Nature, a research group at MIT used single-cell transcriptomics on post-mortem Alzheimer’s brains with and without the APOE4 variant. They found widespread disruption of gene expression across all cell types in the human brain in APOE4 carriers and found a particularly interesting disruption in oligodendrocytes.
Oligodendrocytes are responsible for producing myelin, the protein that forms protective sheaths around nerve fibers. Through single-cell analysis and confirmation in a mouse model, the authors found that APOE4 disrupts cholesterol processing, causing it to accumulate in oligodendrocytes. This prevents the cells from creating protective myelin sheaths, thus slowing cognition and allowing potential damage to nerve fibers.
New Avenues for Alzheimer’s Treatment
The authors treated APOE4-carrying brain cells with cyclodextrin, a drug that stimulates cholesterol removal from the cell. This seemed to improve myelin formation, so the authors also tested cyclodextrin in a mouse model with two copies of APOE4 and once again observed effective flushing out of cholesterol from the brain and improved myelination.
This evidence is further bolstered by results from an Alzheimer’s patient who took cyclodextrin in 2020 under Expanded Access authorization, meaning they had severe disease progression and no alternative treatment options. The company responsible for the one-off trial, Cyclo Therapeutics, reported that the patient remained stable for 18 months following treatment, and they are proceeding with additional trials of cyclodextrin for Alzheimer’s.
Outsourcing Bioinformatics Analysis: How We Can Help
Understanding how APOE4 and other genetic variants actually contribute to disease is critical for discovering new therapeutic avenues across many diseases. Our clients are at the forefront of tackling these kinds of research questions with sophisticated bioinformatics approaches. However, transforming raw sequence data of any kind into actionable biological insights is no small feat.
As experts across data types from cutting-edge sequencing platforms, we can help you tackle the challenging computational tasks of storing, analyzing, and interpreting genomic data. Bridge Informatics’ bioinformaticians are trained bench biologists, so they understand the biological questions driving your computational analysis. Click here to schedule a free introductory call with a member of our team.
Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].