Apolipoprotein E Christchurch variant (APOE-Ch) (APOE-Ch)

The Apolipoprotein E Christchurch variant (R136S) is a rare genetic mutation in the APOE gene, characterized by the substitution of arginine with serine at position 136. This variant was first identified in a patient with Type III hyperlipoproteinemia (Wardell et al., 1987) and later gained significant attention for providing profound resistance to Alzheimer's disease in a patient homozygous for the APOE3 isoform (Arboleda-Velasquez et al., 2019). Biologically, the mutation occurs within the receptor-binding domain of the APOE protein, leading to a marked reduction in its affinity for heparan sulfate proteoglycans (HSPGs) and the low-density lipoprotein (LDL) receptor. In the central nervous system, this impaired binding is hypothesized to prevent the uptake and propagation of pathological tau aggregates, thereby protecting against neurodegeneration even in the presence of extensive amyloid-beta plaques (Nelson et al., 2023). However, in the systemic circulation, the reduced binding affinity hinders the hepatic clearance of lipoprotein remnants, which can result in dyslipidemia and increased cardiovascular risk (Wardell et al., 1987). Current drug development efforts, including monoclonal antibodies like 7C11, aim to mimic the protective effects of the Christchurch mutation by blocking the APOE-HSPG interaction site to treat or prevent Alzheimer's disease (Chen et al., 2024).

Other names

APOE R136SApolipoprotein E2-ChristchurchApolipoprotein E3-ChristchurchAPOE3chArg136Ser variant

Inhibition of the interaction between APOE and heparan sulfate proteoglycans (HSPGs) to reduce tau-mediated neurodegeneration.