ABSTRACTBackgroundAlzheimer's disease (AD) is one of the most common forms of dementia among the elderly in the world. With the increase of human life expectancy, its incidence is also increasing year by year. Tacrine (TAC) is the first acetylcholine inhibitor approved for the treatment of AD. Although TAC has obvious anti‐AD activity, it was eventually delisted due to acute liver injury caused by its strong hepatotoxicity. Rosmarinic acid (RA) has shown good activity in both neuroprotection and hepatoprotection.Purpose and Study DesignIn this study, the combination of RA and TAC was explored, and a high dose of d‐galactose was used to build an AD mouse model, which was given at the same time for 4 weeks in order to alleviate TAC hepatotoxicity and enhance the intervention of AD in mice through RA. In particular, we pay attention to the key role of Aβ and microglia in the pathogenesis of AD, so we evaluate the ability of RA combined with TAC in alleviating chronic neuroinflammation induced by Aβ plaque in the brain of AD mice and enhancing the ability of microglia to clear Aβ plaque.ResultsThe results show that the combination of RA and TAC has the best intervention effect on AD compared with the single use of the two drugs, and it is basically positively correlated with RA dose. RA + TAC significantly improved body weight, organ index, and behavioral state of AD mice. Further analysis showed that RA + TAC enhanced the antioxidant level of hippocampus and serum of AD mice, alleviated the pathological damage of hippocampus, significantly improved cholinergic system, reduced the expression levels of AB plaque and neurotoxic Aβ1‐41 and Aβ1‐42 in the brain, and significantly increased the level of neuroprotective protein trigger receptor expressed on myeloid cells 2 (TREM2), which mediated the phagocytosis of microglia. More importantly, the combination therapy of RA and TAC decreased the expression of M1 microglia marker (ionized calcium–binding adapter molecule 1 [Iba‐1]), increased the expression of M2 microglia marker Arg‐1, and promoted the release of anti‐inflammatory compounds. In addition, RA + TAC also inhibited the mRNA expression of TLR4 and NF‐κB related to neuroinflammation. In the aspect of liver function, RA reduced cell death mediated by Caspase‐3 by regulating the expression of bcl‐2/bax, alleviated TAC‐induced liver injury in mice, and made the serum indexes of ALT, AST, ALP, TBIL, and γ‐GT reflecting liver function closer to the normal range.ConclusionThe combination of RA and TAC shows the potential to reduce the hepatotoxicity of TAC and is expected to enhance its therapeutic effect on AD.