In the central nervous system, myelin consists to multi-layered membrane structure ensheathing neuronal axons, which is necessary for the effective propagation of action potentials along axons, as well as support of axonal energy metabolism and neuronal health. Myelin regulatory factor (MYRF) is endoplasmic reticulum (ER)-anchored transcription factor that translocate from the ER into the nucleus to promote the myelin-related genes. Although, the current evidence reported the dysregulated myelin in patients with mild cognitive impairment and Alzheimer’s disease (AD), MYRF-related neurological mechanisms is still incompletely understood. In this study, we elucidate the interaction between the MYRF expression and multiple AD pathology. The MYRF was significantly upregulated in both AD model mouse and patient brain through the gene expression profiling. The abnormal MYRF induced the various pathological features of AD, including the mitochondrial dysfunction with ATP, ER stress with IRE1α-XBP1 pathway, and aggregated tau with phosphorylation through the activation of mitogen-activated protein kinase (MAPK) signal pathway. Furthermore, aggregated tau enhanced the MYRF mRNA expression that accelerated the pathological features of mitochondria and ER as the vicious cycle. Collectively, these finding demonstrated that MYRF can act the upstream of pathological risk factor, as well as have a potential to be one of the valuable therapeutic factors for AD.