Microglia are thought to modulate Alzheimer’s disease by limiting the spread of amyloid plaques that contribute to disease pathology. To determine the effect of APÖ To genotype microglia function, the authors isolated microglia from APÖ ε3/ε3 or APÖ ε3/ε4 patients with AD and age-matched healthy controls and performed single nucleus RNA sequencing. It was observed that microglia from women who had APÖ ε4 allele was highly enriched for genes associated with degranulation signaling in neutrophils, an important peripheral immune cell type. Neutrophil degranulation signaling was also associated with the severity of tauopathy in women who APÖ ε4 allele, suggesting that neutrophils may contribute to AD risk in these patients.

Next, the authors performed RNA sequencing on neutrophils from men and women with mild cognitive impairment or AD, using samples from cognitively unimpaired individuals as a comparison. Neutrophils from healthy women who had the APÖ The ε4 allele showed signs of accelerated immune aging compared to neutrophils from APÖ ε3/ε3 individuals. In addition, neutrophils from cognitively impaired women who APÖ The ε4 allele showed higher expression of genes associated with signaling of the cytokine interleukin (IL)-17 or immunosuppressive pathways involving IL-10, IL-18 and TGFβ. IL-17⁺ Neutrophils were also better able to enter the brains of APÖ An interaction with microglia was observed in ε3/ε4 women with AD.