Healthcare, UK (Commonwealth Union) – Scientists have uncovered a new clue in understanding why certain individuals are more prone to Alzheimer’s disease.
Recent research from the University of Sheffield’s Institute of Translational Neuroscience (SITraN), in collaboration with the UK Dementia Research Institute at the University of Cambridge, sheds light on the interaction between a risk gene known as apolipoprotein E (APOE) and a protein known as amyloid-beta (Aβ), and how this interaction influences the development of Alzheimer’s disease.
The accumulation of Aβ protein in brain tissue, forming plaques, is a characteristic feature of Alzheimer’s. This buildup begins two to three decades before symptoms appear, serving as one of the earliest indicators of the disease. This process damages brain cells and disrupts their function, leading to symptoms like memory loss. Therefore, preventing this buildup or reducing its toxicity is a potential therapeutic approach.
The APOE gene, located on chromosome 19, has garnered significant attention in the scientific community for its critical role in the development of Alzheimer’s disease. This gene is responsible for producing the APOE protein.
Researchers of the study highlighted the fact that APOE is the most common risk gene associated with Alzheimer’s disease and exists in three forms in humans. APOE2 is linked to a lower risk of developing Alzheimer’s. APOE3, the most prevalent form, does not seem to affect the risk. However, APOE4 significantly causes an elevation of the risk.
Approximately one in seven healthy individuals carries two copies of the APOE4 gene. In contrast, among those diagnosed with Alzheimer’s disease, one in every 2.5 patients carries this gene, underscoring the substantial risk it may have for the condition.
The researchers in Sheffield identified the connection between two primary aspects of Alzheimer’s disease – the inherited APOE gene and the development of Alzheimer’s disease through the regulation of Aβ accumulation. By transforming human skin cells into brain cells and isolating Aβ protein clusters from patients with various APOE gene versions, they discovered that all APOE gene forms interact with Aβ protein during its initial aggregation. Nevertheless, the APOE4 variant of the gene leads to Aβ becoming more detrimental to brain cells and hastens its buildup compared to other gene variants.
The lead author for the research, Dr Suman De from the University of Sheffield, Institute for Translational Neuroscience (SITraN), says “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.”
Recently, the FDA approved two distinct treatments aimed at eliminating amyloid clumps from the brain tissue of Alzheimer’s patients, offering new hope in the fight against this debilitating condition. However, their effectiveness has been described as limited, particularly for patients carrying the APOE4 gene. Researchers of the study indicated that this limitation arises because these treatments are typically administered in the later stages of the disease when many brain cells have already been damaged due to the accumulation of Aβ.
This study sheds light on how APOE affects Aβ clumping in the early stages of Alzheimer’s and demonstrates that selectively removing the harmful Aβ clumps associated with APOE4 could reduce brain cell loss and enhance the removal of amyloid from the brain. Scientists are optimistic that future research may lead to targeted therapies, especially for patients with the APOE4 gene, to slow down or prevent the progression of Alzheimer’s disease. Although still in its early phases, this research marks a significant advancement in our understanding of Alzheimer’s disease.
Dr De says “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.”
The findings appeared in the journal Nature Communications, was carried out in partnership with the University of Cambridge, Washington University School of Medicine, as well as the University of Eastern Finland.
