APOE4's C112R substitution causes aberrant domain interaction altering lipid binding and cholesterol transport. Small molecules (APOE4 correctors like PU-WS13) can shift APOE4 toward APOE3 structure in vitro, improving function. Clinical translation requires demonstrating CNS penetrance, APOE4-selective efficacy, and biomarker-driven patient stratification.
APOE4 differs from APOE3 by C112R causing domain interaction that alters lipid binding and amyloid clearance.