Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioral and psychological symptoms in Alzheimer's disease (AD). However, it is presently unclear whether quetiapine has beneficial effects on memory and whether the effects of quetiapine on psychological symptoms are associated with its effect on memory in AD. The present study was designed to examine the effect of chronic administration of quetiapine on the conditioned (generalized) anxiety that is related to learning experience of open arm exposure in the elevated T-maze (ETM) test in an amyloid precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. In a 2nd experiment, the effect of quetiapine on memory per se was investigated in a Y-maze test in AD mice. Non-transgenic and transgenic mice were treated with quetiapine in drinking water from the age of 2 months. After continuous treatment with quetiapine (5 mg/kg/day) for 10 months, mice were tested for conditioned anxiety on the ETM task. After ETM testing, the expression of brain-derived neurotrophic factor (BDNF), a neuroprotective protein, was examined by immunohistochemistry in the basolateral amygdala (BLA) and hippocampus. In the 2nd experiment, the effect of quetiapine (2.5 or 5 mg/kg/day) on the short-term memory in AD mice was tested in a Y-maze test. After 10 months of administration, quetiapine prevented the decrease of conditioned anxiety and cerebral BDNF in AD mice. In addition, quetiapine also prevented memory impairment in the Y-maze test in AD mice. These findings suggest that the therapeutic mechanism of quetiapine on anxiety in AD may be associated with its beneficial effect on memory and its neuroprotective effect on cerebral BDNF expression.