Recent data propose that Alzheimer’s disease (AD) should be considered as a systemic disease with a strong immune component. However, direct targeting of the immune system contribution to AD has been so far minimally explored. Here, by using a systems biology approach based on network integration of text mining and genomic data, we identified glucose‐6‐phosphate dehydrogenase (G6PD) as a target that may modulate neutrophil function and, in turn, down-regulate the immune system related damage in AD. Pharmacological and siRNA modulation, performed in differentiated HL-60 cells and primary neutrophils, demonstrated that G6PD is a potent activator of NETosis, a process of controlled cell death, whereby a network of genomic DNA and proteins is decondensed and extruded from the neutrophil, worsening the inflammatory state and the clinical course of AD. We identified a likely molecular basis of such exacerbation in the ability of NETosis fibers to physically associate with Aβ1-42 and shift the monomer-to-aggregate equilibrium towards the toxic oligomeric species. To investigate if neutrophil G6PD inhibition provides an advantage in neurodegenerative conditions, we co-cultured primary mouse cortical neurons together with differentiated HL-60 cells, in which NETosis was previously inhibited by a novel, specific G6PD inhibitor. Results showed that G6PD inhibition significantly rescues both the neuron death and synaptic loss caused by activated neutrophils. This correlates with a reduction of Aβ1-42 released by neurons in the co-culture with G6PD inhibited neutrophils. Our data corroborate the important role of neutrophils in AD, and pinpoint G6PD as a promising neuroimmunological therapeutic target.