Background and Purpose The development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I-2 imidazoline receptor ligands have a neuroprotective role in AD. Moreover, co-treatment of AChE inhibitors with neuroprotective agents have shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I-2 ligand, donepezil and their combination in 5XFAD mice. Experimental Approach 5XFAD female mice were treated with low doses (1 mg center dot kg(-1)center dot day(-1)) of LSL60101, donepezil and donepezil plus LSL60101, during 4 weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze and three-chamber tests were used to evaluate the cognitive and behavioural status after treatment. The effects on AD-like pathology were assessed with immunohistochemistry, western blot, ELISA and qPCR. Key Results Chronic low-dose treatment with LSL60101 and donepezil reversed cognitive deficits and impaired social behaviour. LSL60101 treatment did not affect anxiety-like behaviour in contrast to donepezil. In the 5XFAD brains, LSL60101 and donepezil/LSL60101 treatments attenuated amyloid-beta pathology by decreasing amyloid-beta(40) and amyloid-beta(42) levels, amyloid-beta plaque number and tau hyperphosphorylation. These alterations were accompanied by reduced microglia marker Iba-1 levels and increased Trem2 gene expression. LSL60101 and donepezil decreased glial fibrillary acidic protein (GFAP) astrocytic marker reactivity. However, only LSL60101 and donepezil/LSL60101 treatments significantly increased the synaptic marker levels of post-synaptic density protein 95 and synaptophysin. Conclusion and Implications Chronic low-dose treatment with selective I-2- ligands can be an effective treatment for AD and provide insights into combination treatments for symptomatic and disease-modifying drugs.