〔Abstract〕 Objective To investigate the expression differences of helix-loop-helix hand domain family member D 1/2(EFhd1/2) in Alzheimer′s disease(AD) patients and model mice. Methods The expression changes of EFhd1/2 in AD patients were compared by using data from Alzheimer′s disease database(AlzData), and the changes in mRNA levels and protein levels of EFhd1/2 in brain tissues of AD patients and healthy control group were detected by qPCR and Western blot. The changes of EFhd1/2 mRNA and protein expression in brain tissues of AD models and wild-type mice of 3-month-old and 6-month-old were detected. Microglia were isolated from AD models and detected the changes of EFhd1/2 by RNA-sequencing. Results The Analysis of Alzheimer′s Disease Database data showed that the mRNA levels of EFhd1 in AD patients increased, while EFhd2 decreased. AD patients brain tissue samples showed an upward trend in the expression of EFhd1 in different brain regions of AD patients compared with healthy controls, while EFhd2 was not different. In the AD mice model, the mRNA levels of EFhd1 were similar in both 3-month-old and 6-month-old AD mice compared with wild-type mice, but the protein levels of EFhd1 increased; the mRNA levels of EFhd2 increased in 3-month-old AD mice, and protein levels remained similar in the brain tissue from AD mice aged 3 months and 6 months. However, EFhd2 increased in microglia from 6-month-old AD mice. Conclusion EFhd1 increased in both AD model mice and brain tissue of AD patients, suggesting that EFhd1 might play an important role in the development of AD, while EFhd2 increased in microglia in AD model mice, indicating that EFhd2 might be involved in AD related microglia activation and neuroinflammation.