New Clue Found for Why APOE4 Increases Alzheimer’s Risk

Scientists have discovered a key reason why some people are more likely to get Alzheimer’s disease. This new study, published in Nature Communications, reveals how a genetic variant called APOE4 interacts with a protein known as amyloid-beta. This interaction makes it more likely for a person to develop Alzheimer’s disease.

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Understanding Alzheimer’s Disease

Alzheimer’s disease is a serious condition that causes memory loss and cognitive decline. One of the main features of this disease is the buildup of amyloid-beta protein in the brain. These proteins form clumps called plaques, which disrupt brain function.

Role of APOE in Alzheimer’s Disease

APOE is a gene with three common forms: APOE2, APOE3, and APOE4. APOE4 is the most significant genetic risk factor for Alzheimer’s, while APOE2 reduces the risk, and APOE3 has no major impact.

The study aimed to understand how the APOE4 variant affects amyloid-beta buildup in the brain. By clarifying this relationship, researchers hope to find new ways to prevent or treat Alzheimer’s, especially in people with the APOE4 variant.

Research Methods and Findings

Scientists used a novel approach by turning human skin cells into brain-like cells. They then isolated amyloid-beta clumps from the brains of Alzheimer’s patients with different APOE gene variants to see how these clumps interacted with the brain-like cells.

They found that while all APOE variants interact with amyloid-beta, the APOE4 variant causes amyloid-beta to be more toxic and accumulate faster. This increased toxicity and faster accumulation are critical because amyloid-beta plaques are an early indicator of Alzheimer’s, disrupting brain cells and leading to cognitive decline.

One major finding is that APOE4-amyloid-beta clumps are particularly harmful to brain cells. Targeting these clumps could help reduce the damage caused by amyloid-beta and slow its buildup, offering a new path for Alzheimer’s treatments.

Implications for Future Therapies

Focusing on removing or neutralizing these harmful clumps could improve the effectiveness of treatments for Alzheimer’s. Current treatments that target amyloid-beta removal are less effective for APOE4 carriers, especially when given later in the disease. Earlier intervention targeting these specific clumps could be more beneficial.

Lead author Suman De from the University of Sheffield’s Institute for Translational Neuroscience said, “Identifying APOE4-Aβ clumps as a target is exciting. By focusing on removing these clumps, we can reduce the damage to brain cells, enhance the clearance of toxic amyloid-beta, and slow its accumulation. This opens up new possibilities for therapies.”

Study Significance

This study also explains why people with the APOE4 variant are at a higher risk of developing Alzheimer’s. While the risk associated with the APOE gene has been known for decades, this research shows how different variants affect amyloid-beta accumulation and influence the likelihood of developing the disease.

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References

• Xia, Z., Prescott, E. E., Urbanek, A., Wareing, H. E., King, M. C., Olerinyova, A., Dakin, H., Leah, T., Barnes, K. A., Matuszyk, M. M., Dimou, E., Hidari, E., Zhang, Y. P., Lam, J. Y. L., Danial, J. S. H., Strickland, M. R., Jiang, H., Thornton, P., Crowther, D. C., … De, S. (2024). Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease. Nature Communications.
• De, Suman. (2024). “New study sheds light on why APOE4 variant increases Alzheimer’s risk.” Nature Communications.

This new understanding of how APOE4 increases Alzheimer’s risk could lead to more effective treatments and improved quality of life for those affected by the disease.