Lithium has been shown to delay the progression of Alzheimer's disease to reduce the prevalence of dementia. However, its narrow therapeutic index and numerous toxic effects at conventional dosage limited its long-term use to older subjects. Here, we tested the effect of low-dose lithium on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mouse. We found that both chronic and acute administration of lithium dose-dependently increased in blood and brain tissues. Long-term administration of low-dose lithium does not affect the body weight of APP/PS1 mice, but can significantly improve spatial memory of APP/PS1 mice. Pathologically, it also reduced β-amyloid plague and p-tau levels. Therefore, our results show that long-term low-dose lithium can ameliorate cognitive dysfunction and pathological alterations of Alzheimer's disease transgenic mice, and provide a theoretical basis for the further application of low-dose lithium in Alzheimer's disease clinical treatment.