Emerging therapeutic strategies to target APOE4 in Alzheimer's disease.

The apolipoprotein E ε4 (APOE4) allele is the strongest common genetic risk factor for late-onset Alzheimer's disease. However, its incomplete penetrance supports the view that it acts as a modifiable systems-level perturbation of brain homeostasis rather than a deterministic driver. Increasing evidence further positions APOE4 protein within interconnected lipid metabolic pathways, with converging genetic, epidemiological, and translational studies implicating disrupted cholesterol transport, lipoprotein metabolism, and lipid oxidation as upstream mechanisms that promote neurodegeneration. Here, we synthesize currently developing therapeutic strategies targeting APOE4 across domains: small molecules, endogenous protectors, emerging biologics, and systemic lipid modulators. Small molecules include structural correctors and natural compounds, while endogenous protection arises from APOE2, the APOE3-Christchurch variant, and modifiers such as CASP7, KLOTHO, the VHL-HIF axis, fibronectin, and NHE6-mediated endosomal regulation. Biologic platforms enable allele-selective and pathway-specific interventions via siRNA, antisense oligonucleotides, and antibodies targeting pathological APOE conformers. In parallel, cholesteryl ester transfer protein (CETP) inhibition has emerged as a systems-level strategy that restores lipid and redox homeostasis, with early clinical evidence showing reductions in neurodegenerative biomarkers, particularly in APOE4 carriers. These advances support an integrative therapeutic framework to restore brain lipid homeostasis, stress resilience and neural-vascular coupling, positioning APOE4 as a modifiable node within a preventable lipid-vascular-neurodegenerative axis.