APOE gene variants influence metabolic patterns linked to aging and Alzheimer’s risk

A new research paper was published in Aging (Aging-US) Volume 17, Issue 5, on May 3, 2025, titled "APOE genotype and biological age impact inter-omic associations related to bioenergetics."

In this study, led by first author Dylan Ellis and corresponding author Noa Rappaport from the Institute for Systems Biology, researchers discovered that different versions of the APOE gene-particularly ε2 and ε4-are linked to metabolic patterns associated with aging and Alzheimer's disease risk. Both variants were linked to increased levels of diacylglycerols, a type of fat molecule connected to insulin resistance and inflammation, suggesting shared disruptions in how the body regulates energy.

The research team analyzed data from over 2,200 adults without an Alzheimer's diagnosis, exploring how APOE genotypes influence biological age, a measure of health that reflects how quickly or slowly someone is aging at a cellular level. They found that the same metabolic disturbances seen in ε2 carriers were also present in people considered biologically older, revealing unexpected overlap between genetic risk and aging-related metabolic changes.

To examine these connections in more detail, the researchers used a multi-omics approach, combining blood-based metabolism and protein data, gut bacteria analysis from stool samples, and clinical chemistry data. This method allowed them to map how genetic differences and biological aging affect the body's energy systems. They observed altered connections between glucose metabolism, inflammatory markers, and key molecules that play roles in energy production, indicating early disruptions that could contribute to age-related diseases.

One of the study's surprising findings was that the ε2 variant, usually associated with longer life and reduced Alzheimer's risk, showed metabolic traits similar to those found in insulin-resistant individuals. This suggests that ε2 may carry metabolic disadvantages earlier in life, with its protective effects becoming more pronounced later. Conversely, ε4-linked to greater Alzheimer's risk-may exert its influence based on interactions with lifestyle factors like diet, sex, and overall health status.

"'Omics association patterns of ε2-carriers and increased biological age were also counter-intuitively similar, displaying significantly increased associations between insulin resistance markers and energy-generating pathway metabolites."

By identifying these shared biological signatures, this study offers a new framework for understanding how genes and metabolism work together to influence aging. These findings could support more personalized health strategies aimed at delaying biological aging and reducing the risk of chronic diseases. As aging populations grow worldwide, understanding these pathways is essential to improving healthspan.