Beyond the Known and Established Neurodegenerative Effects: Roles of APOE Across a Wide Spectrum of Pathophysiological Condition

ABSTRACT Apolipoprotein E (ApoE) is classically recognized for its role in lipid trafficking and the coordination of lipoprotein metabolism, yet its influence extends well beyond these pathways. While the contribution of ApoE isoforms to neurodegenerative disorders, most notably Alzheimer's disease, has been described in considerable detail, their impact on peripheral physiology is far less clearly defined. Evidence accumulated over the past decade suggests that variation in ApoE may shape traits such as adiposity, fat and lean mass distribution, bone density, muscle function, and cardiovascular risk, although the findings are often inconsistent across studies and populations. This review brings together current knowledge on how ApoE interfaces with several key biological processes, including inflammatory signaling, glucose and insulin responses, mitochondrial and redox homeostasis, senescence, and regulated cell death. These pathways lie at the core of many chronic disorders, yet their links to ApoE genotype remain insufficiently defined. Moreover, translation of these findings, including the use of ApoE genotyping for risk stratification, therapeutic choices, and personalized prevention is also discussed. By reframing ApoE as a systemic regulator rather than a brain‐restricted factor, this review offers a cohesive roadmap for interdisciplinary research and improved clinical interpretability of ApoE‐associated risk.