Rare Variant of APOE Reduces Plaque Formation Associated with Alzheimer’s

What: Chia-Chen (Jenny) Liu, PhD, Guojun Bu, PhD, and colleagues have shown how APOE3-Jacksonville, a rare form of another apolipoprotein E (APOE) gene variant that was previously thought to be neutral for Alzheimer’s, the APOE3 variant, may help protect against Alzheimer’s disease (AD) through changes in brain metabolism.

Where: Liu C.C. et al., “APOE3-Jacksonville (V236E) Variant Reduces Self-Aggregation and Risk of Dementia,” Science Translational Medicine, 2021.

BrightFocus Connection: This project was supported in part by an Alzheimer’s Disease research grant to first author Chia-Chen (Jenny) Liu, PhD, of Mayo Clinic Jacksonville. Her colleague there, senior author Guojun Bu, PhD, is a past BrightFocus grantee and Alzheimer’s Disease Research (ADR) Scientific Review Committee member.

Why It Is Important: There are three variations of the apolipoprotein E gene: APOE2, APOE3, and APOE4. Having the APOE4 version increases the risk that someone will develop Alzheimer’s disease (AD), while having the APOE2 version decreases the risk of developing AD. APOE3 is the most common version and was thought to be neutral. However, in 2014, Dr. Bu’s group discovered another version of APOE3, called APOE3-Jacksonville or APOE3-Jac, that also protects against developing AD.

Apolipoprotein E’s job throughout the body, as well as in the brain, is to carry cholesterol and lipids through the blood. APOE proteins can also play a role in the formation of amyloid-beta (Aβ) plaques, and several groups have shown that APOE4, in particular, is more likely to co-deposit with a type of amyloid-beta protein that deposits in the brain. In the new study, the researchers found that APOE3-Jac lowers the risk of AD by reducing aggregation of all APOE proteins, even APOE4.

The research team first confirmed in human brains that people with the APOE3-Jac variant had fewer and less concentrated plaques than people with the regular APOE3 variant. Then they showed that the protein made from the APOE3-Jac gene reduces aggregation of APOE proteins – including AD-associated APOE4 – and is more capable of binding beneficial lipids that the brain needs to function properly. Finally, the research team used a mouse model of AD to show that mice with APOE3-Jac had fewer Ab plaques and associated brain toxicity.

It is not entirely clear what role Ab plaques play in triggering neurodegeneration and subsequent signs and symptoms of AD, however, the greater plaque build-up, the more likely a person is to have the disease. Learning more about the protective role that APOE3 plays against Aβ plaque formation may pave the way for new therapies. Anti-amyloid drugs continue to be tested in clinical trials and targeting the APOE proteins may be an effective complementary or alternative therapeutic strategy. There may be other strategic treatment uses that are still to be determined.