NLRP3 is activated in Alzheimer's disease (AD) and contributes to pathology in APP/PS1 mice. The study demonstrates that NLRP3 activation is involved in the inflammatory processes driving AD. In human brains with mild cognitive impairment (MCI) and AD, active caspase-1 expression is significantly increased, suggesting a role for the inflammasome in AD. NLRP3-deficient or caspase-1-deficient mice carrying mutations associated with familial AD showed reduced brain caspase-1 and IL-1β activation, enhanced Aβ clearance, and protection from memory loss. These mice also exhibited a shift in microglial cells to an M2 phenotype, leading to decreased Aβ deposition in the APP/PS1 model of AD. These findings indicate that the NLRP3/caspase-1 axis plays a crucial role in AD pathogenesis and suggest that NLRP3 inflammasome inhibition could be a novel therapeutic approach for AD. Chronic Aβ deposition in AD leads to persistent microglial activation, which is associated with increased IL-1β levels. IL-1β is produced as an inactive pro-form and requires caspase-1 for activation and secretion. The NLRP3 inflammasome, which senses inflammatory crystals and aggregated proteins, including Aβ, is involved in several chronic inflammatory diseases. The study assessed caspase-1 cleavage in brains from AD, early-onset AD (EOAD), and MCI patients and found significantly increased cleaved caspase-1 in these patients compared to controls. This increase was mirrored in aged APP/PS1 transgenic mice, which express a human/mouse chimeric amyloid precursor protein and human presenilin-1, leading to chronic Aβ deposition, neuroinflammation, and cognitive impairment. NLRP3-deficient mice crossed into APP/PS1 mice showed reduced caspase-1 cleavage and similar IL-1β levels to wild-type animals. These mice exhibited reduced Aβ deposition and improved memory function. The study also found that NLRP3 deficiency increased microglial Aβ phagocytosis, suggesting that NLRP3 inflammasome activation reduces Aβ clearance. Additionally, NLRP3 deficiency led to a shift in microglial cells to an M2 phenotype, which is associated with increased Aβ clearance and tissue remodeling. These findings suggest that NLRP3 activation contributes to AD pathology by promoting chronic inflammation and impairing microglial clearance functions. The study highlights the potential of targeting the NLRP3 inflammasome as a therapeutic strategy for AD.NLRP3 is activated in Alzheimer's disease (AD) and contributes to pathology in APP/PS1 mice. The study demonstrates that NLRP3 activation is involved in the inflammatory processes driving AD. In human brains with mild cognitive impairment (MCI) and AD, active caspase-1 expression is significantly increased, suggesting a role for the inflammasome in AD. NLRP3-deficient or caspase-1-deficient mice carrying mutations associated with familial AD showed reduced brain caspase-1 and IL-1β activation, enhanced Aβ clearance, and protection from memory loss. These mice also exhibited a shift in microglial cells to an M2 phenotype, leading to decreased Aβ deposition in the APP/PS1 model of AD. These findings indicate that the NLRP3/caspase-1 axis plays a crucial role in AD pathogenesis and suggest that NLRP3 inflammasome inhibition could be a novel therapeutic approach for AD. Chronic Aβ deposition in AD leads to persistent microglial activation, which is associated with increased IL-1β levels. IL-1β is produced as an inactive pro-form and requires caspase-1 for activation and secretion. The NLRP3 inflammasome, which senses inflammatory crystals and aggregated proteins, including Aβ, is involved in several chronic inflammatory diseases. The study assessed caspase-1 cleavage in brains from AD, early-onset AD (EOAD), and MCI patients and found significantly increased cleaved caspase-1 in these patients compared to controls. This increase was mirrored in aged APP/PS1 transgenic mice, which express a human/mouse chimeric amyloid precursor protein and human presenilin-1, leading to chronic Aβ deposition, neuroinflammation, and cognitive impairment. NLRP3-deficient mice crossed into APP/PS1 mice showed reduced caspase-1 cleavage and similar IL-1β levels to wild-type animals. These mice exhibited reduced Aβ deposition and improved memory function. The study also found that NLRP3 deficiency increased microglial Aβ phagocytosis, suggesting that NLRP3 inflammasome activation reduces Aβ clearance. Additionally, NLRP3 deficiency led to a shift in microglial cells to an M2 phenotype, which is associated with increased Aβ clearance and tissue remodeling. These findings suggest that NLRP3 activation contributes to AD pathology by promoting chronic inflammation and impairing microglial clearance functions. The study highlights the potential of targeting the NLRP3 inflammasome as a therapeutic strategy for AD.