FUNCTIONAL IMPACT OF NATURALLY OCCURRING APOE213 VARIANTS IN A RODENT MODEL OF SPORADIC ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a multifactorial disorder in which genetic risk, cognitive decline, peripheral biomarkers, and neuropathology converge. Conventional rodent models often capture isolated AD features but fail to reproduce the natural course of the disease. The South American rodent Octodon degus represents a unique natural model of sporadic AD, exhibiting human-like traits including a long lifespan, diurnal behavior, and naturally occurring genetic variability in Apolipoprotein E (ApoE) (Tan Z., 2022; Hurley M., 2018; Mugnaini M., 2022). Given that ApoE is the strongest genetic risk factor for AD in humans, influencing disease largely through lipid metabolism, naturally occurring ApoE variants in degus offer a valuable opportunity to explore conserved mechanisms of vulnerability.

Here, we investigated whether variation at position 213 of ApoE influences cellular lipid homeostasis. Guided by structural predictions suggesting altered lipid interactions, we focused on two common variants, E and K, resembling wild-type–like and risk-associated states, respectively. Using primary fibroblasts from genotyped animals, we found that ApoE213K cells displayed increased lipid droplet number and size compared to ApoE213E cells, consistent with a disease-associated lipid storage phenotype. Notably, this phenotype mirrors emerging evidence linking human APOE4 to lipid droplet dysfunction in AD.

Building on these findings, we are extending our analyses to peripheral biomarkers (e.g., plasma pTau217), behavioral stratification, and mechanistic pathways such as autophagy and ferroptosis to construct an integrated, multiscale framework of disease vulnerability. Together, this work establishes Octodon degus as a powerful natural model to investigate how ApoE-driven lipid dysregulation contributes to AD risk.