Herein, we report the therapeutic benefit of NLRP3 inflammasome inhibition in Alzheimer’s disease (AD), using a novel and selective brain-penetrant small molecule NLRP3 inhibitor, VEN-02XX, which we profiled in the 5XFAD/Rubicon KO AD model. Here, NLRP3 is linked to early-onset autosomal dominant Alzheimer disease.