Tooth loss is a known risk factor of Alzheimer's disease (AD). However, the association of tooth loss with the molecular pathogenesis of AD is still unknown. The hypothesis that the molecular pathogenesis of AD is enhanced by molar tooth loss was tested. Seventeen female transgenic mice (J20) were divided into the experimental (EX, n = 10) and control (C, n = 7) groups. In the EX group, maxillary bilateral molar teeth were extracted at the age of 6 months. In the C group, however, these teeth remained intact. Passive avoidance test was performed to evaluate learning and memory abilities right after tooth extraction (6 months old) and 4 months later (10 months old). After the test at 10 months, amyloid beta (Aβ) deposition and changes of neuronal cell number and area in the hippocampus were investigated using half of the brains. The other half was homogenized and used to determine Aβ40 and Aβ42 levels by ELISA. At the 10 months of age, learning and memory abilities were significantly impaired in the EX group compared to the C group (P < 0.05). The neuronal cell number in the CA1 and CA3 regions was significantly lower in the EX group than in the C group (P < 0.05). Total Aβ, Aβ40, and Aβ42 levels showed no significant intergroup difference. Molar tooth loss may cause neuronal cell loss in the hippocampus, leading to memory impairment; this process may be independent of the amyloid cascade.