The endotoxin hypothesis of Alzheimer’s disease (AD) posits that lipopolysaccharide (LPS), a component of Gram-negative bacteria, may contribute to AD pathophysiology by elevating LPS levels in the blood and brain through peripheral infections or gut dysfunction. This elevation promotes amyloid pathology, tau pathology, and microglial activation, leading to neurodegeneration. Evidence supporting this hypothesis includes elevated blood and brain LPS levels in AD patients, increased LPS levels or response in AD risk factors, and the induction of Aβ expression, aggregation, inflammation, and neurotoxicity by LPS. Additionally, LPS induces tau phosphorylation, aggregation, and spreading, as well as microglial priming, activation, and neurotoxicity. Blood LPS also induces synapse loss, neuron loss, and memory impairment in AD mouse models and cognitive dysfunction in humans. To test the hypothesis, reducing blood LPS levels or blocking LPS response could be potential treatments. However, limitations include the use of rodent models, which are less sensitive to LPS than humans, and the need for further longitudinal studies to verify the hypothesis.The endotoxin hypothesis of Alzheimer’s disease (AD) posits that lipopolysaccharide (LPS), a component of Gram-negative bacteria, may contribute to AD pathophysiology by elevating LPS levels in the blood and brain through peripheral infections or gut dysfunction. This elevation promotes amyloid pathology, tau pathology, and microglial activation, leading to neurodegeneration. Evidence supporting this hypothesis includes elevated blood and brain LPS levels in AD patients, increased LPS levels or response in AD risk factors, and the induction of Aβ expression, aggregation, inflammation, and neurotoxicity by LPS. Additionally, LPS induces tau phosphorylation, aggregation, and spreading, as well as microglial priming, activation, and neurotoxicity. Blood LPS also induces synapse loss, neuron loss, and memory impairment in AD mouse models and cognitive dysfunction in humans. To test the hypothesis, reducing blood LPS levels or blocking LPS response could be potential treatments. However, limitations include the use of rodent models, which are less sensitive to LPS than humans, and the need for further longitudinal studies to verify the hypothesis.