A recent study has uncovered how the genetic variant APOE4 disrupts the brain’s energy balance, potentially paving the way for new strategies to combat Alzheimer’s disease. Researchers from Aarhus University in Denmark and the Max Delbrück Center in Germany identified the mechanisms by which APOE4 hinders neurons from utilizing alternative energy sources, specifically lipids, when glucose levels are low.
The APOE gene comes in three variants: APOE2, APOE3, and APOE4. While APOE3 is the most common and considered neutral, APOE4 significantly increases the risk of developing late-onset Alzheimer’s. Previous studies established a link between APOE4 and Alzheimer’s, but the underlying mechanisms remained unclear.
Mechanisms of Disruption
The study’s corresponding author, Thomas Willnow, a professor in the Department of Biomedicine at Aarhus University, explained that as people age, their ability to use glucose decreases. This decline forces nerve cells to seek alternative energy sources. The research indicates that APOE4 blocks this process, preventing neurons from effectively utilizing lipids when glucose supply diminishes.
Glucose serves as the primary fuel for the brain, essential for neuronal communication, repair, and overall function. Due to the brain’s limited capacity to store glucose, it relies heavily on a steady supply from the bloodstream, along with a finely tuned system to convert it into usable energy. Aging disrupts this system, leading to insufficient energy, which can impair memory and cognitive function.
In Alzheimer’s disease, this energy crisis escalates, as neurons struggle to metabolize glucose, even when blood sugar levels are normal. Imaging studies consistently reveal reduced glucose metabolism in brain regions critical for learning and memory, suggesting that this failure to utilize fuel is one of the disease’s earliest and most detrimental effects.
Research Findings and Implications
To investigate the failure of energy use in neurons, the researchers employed a combination of human brain tissue, lab-grown brain organoids, and genetically modified mice. They compared the effects of the APOE3 and APOE4 variants on lipid metabolism, neuronal function, and the accumulation of tau and amyloid-beta proteins, which are characteristic of Alzheimer’s pathology.
The study found that APOE4 led to toxic lipid accumulation in neurons. While the APOE protein typically aids in transporting cholesterol and fats within the brain, the APOE4 variant fails to manage lipid transport effectively. This mismanagement results in fat buildup, increasing neuronal stress and susceptibility to damage. Furthermore, excess lipids in astrocytes and microglia trigger inflammatory pathways, contributing to neuronal death and exacerbating amyloid and tau accumulation.
The study also highlighted that APOE4 compromises lysosomal function, the brain’s waste disposal system, leading to ineffective clearance of toxic proteins and damaged fats, accelerating neurodegeneration. Structural analyses revealed that the altered shape of APOE4 causes it to adhere abnormally to cell membranes and lipids, which underpins its malfunction.
Assistant professor Anna Greda, co-lead author of the study, noted, “The pathway enabling nerve cells to burn lipids for energy production doesn’t work with APOE4, because this APOE variant blocks the receptor on nerve cells required for lipid uptake.”
While the study presents significant insights, the researchers acknowledged limitations, primarily stemming from the reliance on lab-based models, which may not fully represent the complexities of human brain function. Additionally, variations in APOE4 effects based on sex and ethnicity were not comprehensively examined.
Despite these challenges, the findings suggest new therapeutic avenues. Understanding that APOE4’s toxicity arises from mismanaged lipids and inflammation opens potential drug targets focusing on lipid metabolism and lysosomal repair.
Jemila Gomes, another lead author and postdoctoral researcher in Willnow’s lab, emphasized the importance of lipid metabolism, stating, “Our research suggests that the brain is highly dependent on being able to switch from glucose to lipid as we age. Individuals who are carriers of the APOE4 gene may be compromised in this capacity, increasing their risk of nerve cell starvation and death during aging.”
Some research teams are already exploring the potential of “APOE4 stabilizers” that could enable this gene to function more like its neutral counterpart, APOE3. Additionally, since lipid metabolism plays a role, dietary factors and cholesterol management may influence disease progression in APOE4 carriers.
This groundbreaking study was published in the journal Nature Metabolism, marking a significant advance in understanding the relationship between genetics and Alzheimer’s disease.
