Scientists have uncovered a significant clue to understanding why some individuals are more susceptible to Alzheimer’s disease. Published in the journal Nature Communications, this new research reveals how a genetic variant called apolipoprotein E (APOE) interacts with a protein known as amyloid-beta. This interaction influences the likelihood of developing Alzheimer’s disease. Specifically, the study highlights that the APOE4 variant increases the harmful effects of amyloid-beta accumulation in the brain, providing a potential target for new therapies.
Alzheimer’s disease is a debilitating neurodegenerative condition characterized by memory loss, cognitive decline, and personality changes. A key hallmark of the disease is the buildup of amyloid-beta protein in the brain, forming clumps known as plaques, which start accumulating decades before symptoms appear. These plaques disrupt brain cell function and contribute to the disease’s progression.
APOE is the most significant genetic risk factor for Alzheimer’s, with three common forms: APOE2, APOE3, and APOE4. While APOE2 is associated with a reduced risk, and APOE3 has no significant impact, APOE4 dramatically increases the risk of developing Alzheimer’s.
The researchers aimed to understand how the APOE4 variant affects amyloid-beta accumulation and toxicity in the brain. By clarifying this relationship, they hoped to identify new therapeutic targets that could potentially slow or prevent the onset of Alzheimer’s disease, particularly for individuals with the APOE4 variant.
To investigate this, the scientists employed a novel approach by converting human skin cells into brain-like cells, creating models that mimic the human brain environment. They isolated amyloid-beta clumps from the brains of Alzheimer’s patients with different APOE gene variants. They then examined how these clumps interacted with the brain-like cells.
The researchers found that all forms of the APOE gene interact with amyloid-beta during its early stages of accumulation in the brain. However, the APOE4 variant stands out because it causes amyloid-beta to become more toxic to brain cells and accelerates its buildup more rapidly than the other variants, APOE2 and APOE3.
This increased toxicity and accelerated accumulation are crucial because amyloid-beta plaques, which begin forming decades before symptoms of Alzheimer’s appear, are one of the earliest indicators of the disease. The damaging effects of these plaques disrupt brain cell function, leading to cognitive decline and memory loss characteristic of Alzheimer’s disease.
One of the most significant findings of the study is the identification of specific harmful clumps, or aggregates, formed by the interaction of APOE4 with amyloid-beta. These APOE4-amyloid-beta aggregates were shown to be particularly damaging to brain cells, suggesting that they play a pivotal role in the progression of Alzheimer’s.
By focusing on these harmful aggregates, the researchers propose that therapies targeting the removal or neutralization of APOE4-amyloid-beta clumps could mitigate the damage amyloid-beta causes to brain cells. This approach has the potential to enhance the clearance of toxic amyloid-beta and slow down its accumulation, opening new avenues for therapeutic strategies against Alzheimer’s disease.
Suman De from the University of Sheffield’s Institute for Translational Neuroscience, the lead author of the study, explained: “What’s particularly exciting about our findings is that we have identified a specific target – APOE4-Aβ co-aggregates or clumps. By focusing on removing these clumps, we can mitigate the damage amyloid-beta causes to brain cells, enhance the clearance of toxic amyloid-beta, and potentially slow down its accumulation. This opens up potential for new therapies that target these specific protein clusters, offering a new avenue for combating Alzheimer’s disease.”
The study also highlighted the limitations of current treatments that target amyloid-beta removal in the brain. Although recent therapies have shown some promise, their effects are modest, especially for patients carrying the APOE4 gene. These treatments are typically administered in the later stages of the disease when significant brain cell damage has already occurred due to Aβ buildup. The findings from this study suggest that earlier intervention targeting the specific harmful aggregates formed by APOE4 and amyloid-beta could be more effective in slowing or preventing the progression of Alzheimer’s disease.
De added: “This discovery explains why individuals with a specific variant of the inherited APOE gene are at a much higher risk of developing Alzheimer’s. Although this risk associated with the APOE gene has been known for decades, our study illuminates the specific mechanisms by which different variants of the APOE gene influence the accumulation of amyloid-beta and thus affect the likelihood of developing the disease.”
The study, “Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease,” was authored by Zengjie Xia, Emily E. Prescott, Agnieszka Urbanek, Hollie E. Wareing, Marianne C. King, Anna Olerinyova, Helen Dakin, Tom Leah, Katy A. Barnes, Martyna M. Matuszyk, Eleni Dimou, Eric Hidari, Yu P. Zhang, Jeff Y. L. Lam, John S. H. Danial, Michael R. Strickland, Hong Jiang, Peter Thornton, Damian C. Crowther, Sohvi Ohtonen, Mireia Gómez-Budia, Simon M. Bell, Laura Ferraiuolo, Heather Mortiboys, Adrian Higginbottom, Stephen B. Wharton, David M. Holtzman, Tarja Malm, Rohan T. Ranasinghe, David Klenerman, and Suman De.