Project Summary/Abstract Apolipoprotein E (APOE), a major apolipoprotein in the brain, transfers cholesterol and lipids through cell surface receptors and maintains lipid homeostasis. APOE polymorphism is also linked to the genetic risk factor for Alzheimer’s disease (AD). For decades, APOE2 has been considered the most protective APOE isoform among the major 3 APOE isoforms, whereas APOE4 accelerates AD pathologies in both human and mouse animal models. In addition, the recent case report has shown that APOE3 Christchurch mutation, a rare APOE variant, could be a beneficial genetic modifier against AD progression. However, the exact function of the APOE Christchurch mutation and its role in AD pathologies are not clearly understood. It has been well studied that APOE isoforms have differential effects on amyloid-β (Aβ) pathology and the lipidated status of APOE has been involved in Aβ deposition. In addition to Aβ pathology, the recent study suggested APOE isoform modulates tau pathology and tau-related neurodegeneration. In this proposal, we pursue to investigate the roles of APOE Christchurch mutation in AD pathologies. We hypothesized that APOE Christchurch mutation provides beneficial effects against AD progression by modulating lipidation of APOE. APOE Christchurch mutation could impact both Aβ plaque burden and tau-related pathology. The goal of this proposal to determine how APOE Christchurch mutation interact to suppress the pathologies caused by Aβ and Tau.