New clue in understanding increased Alzheimer’s risk

Research from the University of Sheffield’s Institute of Translational Neuroscience (SITraN), together with scientists from the UK DRI at Cambridge, reveals how a protein known as apolipoprotein E (APOE) interacts with amyloid-beta, and how this interaction affects the likelihood of developing Alzheimer's disease. The study is published in the journal Nature Communications.

The APOE gene is the most common risk gene linked to Alzheimer's, and there are three common forms in humans. APOE2 is associated with a reduced risk of developing Alzheimer's. APOE3, the most common form, doesn't appear to affect the risk of the disease. APOE4 increases the risk significantly. About one in seven healthy individuals carry two copies of the APOE4 gene. Among people diagnosed with Alzheimer’s, two of every five people carry this gene.

The scientists connected two fundamental processes in Alzheimer’s - how the inherited APOE gene is linked with developing Alzheimer’s by modulating how amyloid-beta accumulates. They found that all forms of the APOE interact with amyloid-beta during its early accumulation stages. However, the high risk APOE4 variant causes amyloid-beta to become more harmful to neurons, and accelerates its buildup compared to the other variants of the gene.

This study provides an understanding of how APOE influences amyloid-beta build-up during the early stages of disease and shows that selectively removing the harmful amyloid clumps that APOE4 interacts with could mitigate neuronal loss and accelerate the clearance of amyloid from the brain.

Lead author of the study, Dr Suman De from the University of Sheffield’s SITraN, was formerly a postdoctoral researcher in Prof David Klenerman’s lab at the UK DRI at Cambridge, and a recipient of UK DRI Pilot Award funding, for his work investigating APOE4. He 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 Aβ causes to brain cells, enhance the clearance of toxic Aβ, 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.”

Scientists hope future research may lead to targeted therapies, especially for patients with the APOE4 gene, to slow or prevent the progression of Alzheimer's.

Dr 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 Aβ and thus affect the likelihood of developing the disease."

Source: University of Sheffield

To find out more about Prof David Klenerman’s research, visit his UK DRI profile. To keep up to date with the latest UK DRI news and events, sign up to receive our monthly newsletter.

Article published: 20 June 2024
Banner image: Shutterstock/Kateryna Kon