Alzheimer's disease (AD) is one of the most common and devastating aging-related neurodegenerative diseases. Besides the well-known role of chemokines and their receptors in the immune system, they are widely expressed in the nervous system, where they play roles in the regulation of cell migration and neurotransmission. The chemokine CXC motif receptor 4 (CXCR4) is evolutionarily highly conserved seven-transmembrane G-protein-coupled receptors (GPCRs). It has been demonstrated that CXCL12/CXCR4 signaling pathway involved in the pathologic process of AD. In this review, we demonstrated the GPCR family proteins and summarized the relationship between CXCR4 and GPCR, CXCR4 and AD. The review aimed to provide the novel insight of CXCR4 into the early prevention of mild cognitive impairment and in the diagnosis and treatment of AD.