One of the major neurodegenerative diseases, Alzheimer’s disease (AD) is more often characterized by the aggregation of abnormal protein, including tau and amyloid-β, leading to symptoms such as memory impairment and cognitive decline. Several risk factors related to AD progression have been identified through high-throughput sequencing. Here, a regulatory candidate, basigin is a high expression in the prefrontal cortex and hippocampus, and it has categorized as a member of the immunoglobulin superfamily. Basigin plays a role in the subtype of γ-secretase, ischemic stroke progress, cancer progress, and angiogenesis. Therefore, we hypothesized that dysregulation of basigin may be involved in AD. Particularly, we investigated how the downregulation of basigin affects AD and the processes involved. To explain the role of basigin, lentivirus was used to knockdown basigin in mouse primary cortical neuron. Our results revealed that basigin knockdown significantly decreased the expression of synapse formation-associated genes and mitochondrial function-associated genes, as analyzed by mRNA-seq. Subsequently, we confirmed that synaptic dysfunction was caused by reduced basigin expression and also observed mitochondrial dysfunction. In addition, we also showed that this induced an increase in tau aggregation and phosphorylation, which are among the pathological hallmarks of AD. This study suggests basigin might have potential as a diagnostic marker in AD.