Scope As a natural dietary low‐molecular‐weight thiol, pantethine helps maintain brain homeostasis and function in Alzheimer's disease (AD) mice. The current study aims to investigate the protective effects and underlying mechanisms of pantethine on the mitigation of cognitive deficits and pathology in a triple transgenic AD mouse model. Methods and results Compared to control mice, oral administration of pantethine improve spatial learning and memory ability, relieve anxiety, and reduce the production of amyloid‐β (Aβ), neuronal damage, and inflammation in 3×Tg‐AD mice. Pantethine reduces body weight, body fat, and the production of cholesterol in 3×Tg‐AD mice by inhibiting sterol regulatory element‐binding protein (SREBP2) signal pathway and apolipoprotein E (APOE) expression; lipid rafts in the brain, which are necessary for the processing of the Aβ precursor protein (APP), are also decreased. In addition, pantethine regulates the composition, distribution, and abundance of characteristic flora in the intestine; these floras are considered protective and anti‐inflammatory in the gastrointestinal tract, suggesting a possible improvement in the gut flora of 3×Tg‐AD mice. Conclusion This study highlights the potential therapeutic effect of pantethine in AD by reducing cholesterol and lipid raft formation and regulating intestinal flora, suggesting a new option for the development of clinical drugs for AD.

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