Alzheimer’s disease (AD) is characterized by the accumulation of amyloid beta in the brain, forming plaques, along with the presence of tau tangles. In addition to these pathological hallmarks, the role of innate immunity, which acts as the body’s initial defense mechanism, has been implicated in contributing to the development and progression of AD. One key player in this process is gamma–secretase, a protease responsible for generating amyloid beta peptides that are known to play a causative role in AD. Microglial cells, which are the resident immune cells of the brain, undergo significant changes in response to AD pathology. They respond by eating and clearing amyloid beta plaques, indicating their crucial role in modulating the disease. We have discovered that interferon-induced transmembrane protein 3 (IFITM3) functions as a gamma–secretase modulatory protein. Furthermore, we have demonstrated that IFITM3 plays a vital role in regulating and influencing the function of microglia. To further investigate the mechanism of IFITM3 in microglia, we will use an integrated approach that combines chemical biology, genetic techniques, stem cells and animal models. This multidisciplinary approach will allow us to decode the precise role of IFITM3 in microglia and better understand how it influences AD pathology. The ultimate goal of this research is to gain a more comprehensive understanding of IFITM3’s role in microglia, which may pave the way for the development of more effective therapies for AD.