APOE-Targeted Therapeutics for Alzheimer's Disease

Apolipoprotein E (APOE) is the major lipid transport protein in the brain. Produced primarily by astrocytes and microglia, it delivers cholesterol and other lipids for membrane repair, synaptic maintenance, and immune regulation. Through interactions with specific lipid receptors, APOE maintains neuronal and vascular health. The <i>APOE</i> ε4 allele (APOE4), carried by approximately one-quarter of the population, has an altered protein conformation, which reduces lipid transport efficiency and modifies receptor binding. These changes disrupt lipid homeostasis, increase risk of chronic unresolved neuroinflammation and vascular inflammation, and cause breakdown of the blood-brain barrier (BBB), thus increasing neuronal vulnerability to disease pathology and elevating risk for Alzheimer's disease (AD). In this review, we organize the effects of APOE4 into three interconnected "hits" that modulate disease progression: disrupted lipid handling, neurovascular inflammation, and neuronal dysfunction. These interconnected hits help explain why amyloid- and tau-directed therapies alone have modest success in treating AD, particularly in APOE4 carriers. We review emerging APOE-related therapeutic strategies designed to address these mechanisms directly, including structure correctors to restore normal protein folding, agents that enhance lipidation and receptor-mediated lipid transport, approaches that modulate downstream inflammatory responses, and gene therapies aimed at isoform switching or allele silencing. By aligning therapeutic strategies with specific aspects of APOE4 biology, such approaches have the potential to provide broader and safer benefits, complement existing disease-modifying therapies, and improve outcomes for individuals at heightened genetic risk of AD.