2025 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

AD-protective regulatory APOE variation in ethnically diverse populations

How do different Alzheimer’s-linked genes lead to protein changes in global populations?

Olena Korvatska, PhD
University of Washington
Seattle, WA - United States

Background

Genes play an important role in Alzheimer’s. The apolipoprotein E (APOE) gene provides instructions for making ApoE protein. There are several genetic variations of APOE, and the APOE-e4 variation is thought to increase people’s risk of developing Alzheimer’s, in some populations.

However, how the ApoE protein forms its shape and structure is driven by how the cell translates it from a gene to a protein, and there are a number of steps along this process, including how it is cut and ultimately assembled (folded) into its shape. This is related to a process known as alternative splicing and can happen at different stages in translating from a gene to a protein.  In preliminary research, Dr. Olena Korvatska studied APOE ribonucleic acid (RNA) splicing—RNA is a molecule that helps produce proteins from genes and is an important step in the translation process. From 300,000 samples, they identified potential splice sites in the APOE RNA. They analyzed 2,400 variations in the APOE gene from databases of over 800,000 human samples and identified 326 gene variations that are likely to impact APOE splicing. 

These different forms (by shape, size and structure) of ApoE can act differently in the brain. Research indicates that even when genes are the same between people, people with Alzheimer’s have different ApoE protein splice variants than people without Alzheimer’s. These different forms could lead to Alzheimer’s-related changes in the brain.

Research Plan

Dr. Korvatska and colleagues will use advanced computer technology to identify potential ApoE forms and structures in samples from different parts of the brain that are crucial for Alzheimer’s. They will use brain samples of individuals who lived with Alzheimer’s and those who did not, and ensure that they are using samples from individuals with different ancestral backgrounds. Part of their work will also look for whether they can find additional ApoE splice variations, including those that do not typically occur.

Impact

Results from this study may give a comprehensive look at the potential protein variations that arise from APOE gene variations and a better understanding of their role in disease. This could help better understand why some populations with APOE gene variations are at higher risk for Alzheimer’s than others.