How Does a Rare APOE3 Variant Decrease Alzheimer’s Disease Risk?

Post by D. Chloe Chung

The takeaway

The protective APOE3-Jacksonville (APOE3-Jac) genetic variant can substantially lower the risk of Alzheimer’s disease (AD) by reducing protein aggregation and promoting lipid binding and transport.

What's the science?

Apolipoprotein E (APOE) is a lipid-binding protein that transports lipids and mediates fat metabolism. To date, the APOE4 variant is the biggest risk factor for late-onset Alzheimer’s disease (AD), while the APOE3 is the most common variant among populations. A few years ago, the rare variant termed APOE3-Jacksonville (APOE3-Jac) was found to be largely protective against AD, but it was unclear how it can reduce the risk of developing AD. This week in Science Translational Medicine, Liu and colleagues showed that this protective variant aggregates much less while promoting more lipid-binding.

How did they do it?

The authors surveyed three additional cohorts of brain tissues from healthy controls and dementia patients (with AD or Lewy body dementia) to confirm the association between the APOE3-Jac variant and protection against AD. From some of these brain tissues, the authors isolated APOE and amyloid-beta protein, one of the proteins that characteristically aggregates in AD brains, and examined changes in the degree of protein aggregation between people with or without the APOE3-Jac variant. They also used APOE proteins produced by the human cell line and tested whether the APOE3-Jac variant possesses different self-aggregation properties. To investigate whether this variant can have changes in its functional role (e.g., lipid-transporting capacity), the authors cultured astrocytes (the major cell type that produces APOE) isolated from the APOE-knockout mice and treated them with purified human APOE3 or APOE3-Jac proteins. Additionally, the authors injected virus expressing either APOE3 or APOE-Jac into the AD mouse model displaying the amyloid pathology to test how APOE-Jac can impact amyloid aggregation and associated pathological features.

What did they find?

From the additional sequencing of brain tissue, the authors found five no-disease cases with the APOE3-Jac variant but none in the dementia cases, confirming that the variant was strongly associated with the reduced risk of AD. Interestingly, both APOE and amyloid-beta proteins were found to be less aggregated in the brain tissues of the APOE3-Jac carrier compared to those without this variant. Purified APOE proteins also showed that APOE3-Jac forms much fewer oligomers than the normal APOE3, further suggesting that APOE3-Jac has a dramatically reduced tendency to self-aggregate. Additionally, experiments using cultured mouse astrocytes showed that APOE3-Jac was much more efficient in mediating lipid transport than the normal APOE3. The viral expression of APOE3-Jac in the AD mice significantly reduced the amount of amyloid-beta plaques, dying neuronal processes, and neuroinflammatory markers, demonstrating the protective role of the APOE3-Jac variant against AD.

What's the impact?

This study is the first to investigate the mechanisms of APOE3-Jac protection against AD. Also, the APOE3-Jac variant is the first mutation within the gene region critical for APOE’s self-oligomerization and lipid metabolism. It will be interesting to further investigate how this variant can impact pathological changes in the microtubue-associated protein tau, another key disease feature in AD. Findings from this study highlight the therapeutic potential of targeting APOE self-aggregation and APOE-mediated lipid metabolism in AD patients.

Liu et al. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Science Translational Medicine (2021). Access the original scientific publication here.