A recent study published in Nature Medicine uncovers a novel sex-dependent mechanism involving the apolipoprotein E ε4 (APOE4) and in particular neutrophils and their signaling to microglia, which then would mediate cognitive decline in late-onset Alzheimer’s disease (AD).1 We here put the main findings into perspective with current knowledge about APOE4 genotype and neutrophils in the pathogenesis of AD and related tauopathies, and discuss future research directions and therapeutic implications. This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.