Objective To investigate the effects of administration of low dose citalopram in early stage on the learning, memory, and pathological changes of amyloid β-protein (Aβ) of mice with Alzheimer disease (AD). Methods Thirty 5-month-old APP23 transgenic mice were randomly divided into the citalopram group (n=15) and control group (n=15). Mice of the citalopram group were intraperitoneally injected with 10 mg/kg citalopram for 3 months and mice of the control group were intraperitoneally injected with the same volume of normal saline for 3 months. Morris water maze test was adopted to determine the learning and memory functions 24 h after the final injection. Mice were sacrificed and brain tissues were obtained after the final Morris water maze test. Aβ40 and Aβ42 levels of brain tissues were detected by the ELISA. The amount of senile plaques was counted by the immunohistochemical staining. The expression levels of amyloid precursor protein (APP), β-site APP-cleaving enzyme (BACE1), and β-CTF C99/C89 of hippocampus tissues were determined by the Western blotting. Results Compared to the control group, the escape latency of the citalopram group was significantly shorter; total swimming distance decreased; the number of crossing the platform increased (P<0.05); Aβ40 and Aβ42 levels were significantly lower; and the number of senile plaques significantly decreased (P<0.05). But the expressions of APP, BACE1, and β-CTF did not change significantly (P>0.05). Conclusion Long-term administration of low dose citalopram in early stage can improve the learning and memory functions of mice with AD and decrease Aβ neuropathies. The mechanism may be relevant to the up-regulation of expression of α-secretase and enhancing the metabolism of APP in this splicing pathway by citalopram.