AbstractBackgroundLocomotion deficits have emerged as a novel predictor of the pathological progression of the Alzheimer’s disease (AD). In this study, we hypothesize that spinal cord is impacted by the protein pathogenic in the AD.MethodTo rule out the impact of the supraspinal structures, we transected spinal cord completely at thoracic level 10 to cut off all connections between the lumbosacral spinal cord and all the rostral parts of the central nervous system (CNS). The short‐term plasticity of the lumbosacral locomotor circuit was evaluated by an instrumental learning model, paw withdrawal paradigm (PaWL) and the long‐term plasticity was investigated by weekly bipedal treadmill stepping paradigm, which lasted for seven weeks.ResultBoth 4mon and 13mon J20 mice showed significant decreases in the PaWL compared to their WT littermates (p = 0.0075). The spontaneous bipedal locomotion recovery was also blocked in spinal J20 mice when compared to WT littermates (p = 0.0031). These impairments of lumbar circuit plasticity were reversed by the administration of a gamma‐secretase inhibitor (Benzodiazepine‐type LY‐411575) in the spinal J20 mice, suggesting the generation of amyloid beta in local spinal cord circuit contribute to the locomotor deficits.ConclusionThe soluble beta amyloid expression levels in the lumbar spinal cord impair both the the long‐term and short‐term neuroplasticity of locomotion.