Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer’s Disease Drug Candidate

Apolipoprotein E (APOE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer’s Disease (AD). Although APOE4 differs from its non-pathological APOE3 isoform only by the C112R mutation, the mechanism of its proteinopathy is poorly understood. Here, we combine experimental and computational techniques to uncover a “domino-like” effect of C112R mutation on APOE4 behavior. We found that C112R substitution in APOE4 induces long-distance (>15 Å) conformational changes leading to the formation of a T-shaped dimeric unit that is geometrically different and more aggregation-prone than the APOE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce APOE3-like conformational behavior in APOE4 and suppress its aggregation propensity. Analysis of APOE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol. Overall, our results connect the APOE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.