ApoE4 as a Therapeutic Target in Epilepsy: From Pathogenic Mechanisms to Precision Medicine.

Abstract

Background: Epilepsy is a heterogeneous central nervous system disorder characterized by recurrent seizures and is frequently accompanied by cognitive and neuropsychiatric comorbidities. Although apolipoprotein E4 (ApoE4) is well established as a genetic risk factor in Alzheimer's disease, its role as a modifier of epilepsy susceptibility, progression, and therapeutic response remains incompletely understood.

Objective: This review aims to summarize current evidence regarding the molecular mechanisms, clinical implications, and therapeutic potential of ApoE4 in epilepsy, with emphasis on its relevance to precision medicine.

Methods: A narrative review was conducted by synthesizing preclinical and clinical studies investigating the relationship between ApoE4 and epilepsy, including mechanisms related to neuroinflammation, synaptic dysfunction, lipid metabolism, blood-brain barrier (BBB) integrity, clinical phenotypes, and targeted therapeutic strategies.

Results: ApoE4 contributes to epileptogenesis through multiple interconnected pathways. It promotes neuroinflammatory responses by activating microglia and inflammatory signaling, disrupts synaptic plasticity through N-methyl-D-aspartate receptor dysfunction and excitation-inhibition imbalance, impairs lipid and energy metabolism leading to neuronal hyperexcitability, and compromises BBB integrity. Clinically, ApoE4 carriers show increased seizure susceptibility, accelerated cognitive decline, hippocampal atrophy, and variable responsiveness to antiseizure medications. Emerging therapeutic approaches include ApoE4 structural correction, modulation of metabolic and inflammatory pathways, and gene-based interventions.