Engineered Apolipoprotein E4-Neutralizing Shuttle Peptides

**Molecular Mechanism and Rationale** The apolipoprotein E4 (ApoE4) isoform represents the most significant genetic risk factor for late-onset Alzheimer's disease, present in approximately 40-65% of patients compared to 15% of the general population. Unlike the protective ApoE2 and neutral ApoE3 isoforms, ApoE4 exhibits distinct structural conformational changes that drive pathological cascades in neurodegeneration. The proposed engineered ApoE4-neutralizing shuttle peptides exploit the endogen...