Here we show that the fenamate class of NSAIDs inhibit the NLRP3 inflammasome via reversible blockade of volume-regulated anion channels (VRAC) in the plasma membrane, and inhibit cognitive impairments in models of Alzheimer's disease in rodents, thus offering a safe and rapidly translatable option to treat NLRP3-related inflammatory diseases. This evidence concerns the gene NLRP3 and early-onset autosomal dominant Alzheimer disease.