Long-term running exercise (3 months, voluntary wheel running) significantly improved cognitive function in APP/PS1 mice (p < 0.05), increased hippocampal glucose metabolism (p < 0.01) and microglial GLUT5 expression (p < 0.05), enhanced microglial morphological plasticity (p < 0.05), maintained TREM2 protein levels, and reduced sTREM2 release (p < 0.05), alleviating AD-related pathology and cognitive impairment by promoting glucose metabolism. This evidence concerns the gene SLC2A5 and Cognitive impairment.