〔Abstract〕 Objective To investigate the effects of nuclear respiratory factor 1(NRF1) on mitochondrial and cognitive dysfunction in Alzheimer's disease(AD) model mice. Methods The 5×FAD mice were utilized as a model for Alzheimer's disease, and the sparsely labeled AAV virus overexpressing NRF1(AAV-NRF1) was administered via stereotaxic injection into the brain. The expression of NRF1 in hippocampus was determined by Western blot, the morphology of mitochondria in hippocampus was observed by transmission electron microscope, the dendritic spines of sparsely labeled neurons in the CA1 region were visualized and quantified using confocal laser microscopy, cognitive and memory functions of mice were evaluated using the Morris water maze test, while electrophysiological methods were employed to detect long-term potentiation(LTP) of synaptic efficacy. Results The expression of NRF1 in the hippocampus was significantly upregulated following stereotactic injection of AAV-NRF1(P<0.001). This intervention led to notable improvements in mitochondrial morphology within hippocampal neurons, as well as enhanced cognitive and memory functions in mice(P<0.01). Moreover, there was a significant increase in dendritic spine density among neurons located in the CA1 region of the hippocampus(P<0.001), accompanied by long-lasting and stable long-term potentiation(LTP) and a substantial elevation in fEPSP slope(P<0.01). Conclusion The overexpression of NRF1 in a 5×FAD mouse model of Alzheimer's disease(AD) initiated the restoration of mitochondrial dysfunction and enhanced synaptic plasticity, indicating that these alterations may contribute to the therapeutic efficacy of NRF1 overexpression in ameliorating cognitive dysfunction associated with AD.