AbstractMechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135APOEɛ2/ɛ3 carriers. Complement pathway genesC4AandC4Bwere among the most significantly differentially expressed genes between ɛ2/ɛ3 AD cases and controls. We also identified anAPOEε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genesC4A, C4B, andHSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting thisAPOEɛ2 related co-expression network may primarily be involved with tau pathology.HSPA2expression was oligodendrocyte-specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect ofAPOEε2 for AD.