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2020 Zenith Fellows Award Program (ZEN)

ENIGMA-APOE2 : A global Study of the Alzheimer's Protective Genotype

What are the biological mechanisms by which the APOE-e2 genetic change protects against Alzheimer’s risk?

Paul Thompson, Ph.D.
University of Southern California
Los Angeles, CA - United States


The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein that is thought to help carry fats throughout the body. Each person has two copies of APOE in their DNA. There are several variations of the APOE gene including APOE-e2, APOE-e3 and APOE-e4. Possessing APOE-e4 compared to the other variations increases a person’s risk of developing Alzheimer’s and this risk is further increased in the individual who has two copies of APOEe4. The APOE-e2 genetic change is thought to reduce risk of Alzheimer’s. Although APOE-e2 appears to be protective, researchers know very little about how this genetic change alters a person’s overall brain function and brain aging.

Ten years ago, Dr. Paul Thompson and colleagues launched the ENIGMA Consortium to perform large-scale brain scan and genetic studies. The international effort brings together experts in neurology, psychiatry, and other related fields to answer fundamental questions in brain biology. Leveraging data from the ENIGMA Consortium, Dr. Thompson and colleagues will now launch the ENIGMA-APOE2 initiative, a global brain aging study across 35 countries. This will enable the researchers to investigate new questions about the protective effects of APOE-e2, in diverse populations worldwide.


Research Plan

The researchers will collect brain aging metrics including different types of brain scans to measure the brain volume as well as measures to detect brain electrical activity from over 30,000 ENIGMA Consortium participants worldwide who have the APOE-e2 genetic change. Dr. Thompson will examine how brain changes in these individuals compare to those with other types of APOE genetic change, such as APOE-e4. The researchers will also assess sex-specific differences in Alzheimer’s risk.
Furthermore, Dr. Thompson’s team will assess how APOE-e2 may protect the brain from aging. Finally, the researchers will measure changes in other genes in individuals with APOE-e2, to identify previously unknown biological markers (biomarkers) associated with Alzheimer’s risk.


This large population study may help in understanding the role of APOE-e2 in protecting individuals against Alzheimer’s risk. Results from the study could shed light on when and where this genetic change impacts other brain functions and could serve as a standard for future brain aging research involving individuals with APOE-e2. The study may also reveal other key biomarkers as well as sex-specific differences that could be used to understand an individual’s risk of developing, or preventing Alzheimer’s.

Made possible through the generous funding from the Zenith Society, benefiting the Alzheimer’s Association.

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