Alzheimer's disease (AD) is the most common fatal neurodegenerative disease of the elderly worldwide. The identification of AD biomarkers will allow for earlier diagnosis and thus earlier intervention. The aim of this study was to find such biomarkers. It was observed that the expression of Alix was significantly decreased in brain tissues and serum samples from AD patients compared to the controls. A significant correlation between Alix levels and cognitive decline was observed (r = 0.80; p < 0.001) as well as a significant negative correlation between Alix and Aβ40 in serum levels (r =-0.60, p < 0.001). The receiver operating characteristic curve (ROC) analysis showed the area under the curve (AUC) of Alix was 0.80, and the optimal cut-off point of 199.5 pg/ml was selected with the highest sum of sensitivity and specificity. The diagnostic accuracy for serum Alix was 74%, with 76% sensitivity and 71% specificity respectively, which could differentiate AD from controls. In addition, the expression of Alix was found to be significantly decreased in AD compared to vascular dementia (VaD). ROC analysis between AD and VaD showed that the AUC was 0.777, which could be indicative of the role of serum Alix as a biomarker in the differential diagnosis between AD and VaD. Most surprisingly, the decreased expression of Alix was attenuated after the treatment of Memantine in different AD animal models. In conclusion, our results indicate the possibility of serum Alix as a novel and non-invasive biomarker for AD for the first time.Copyright © 2021 Sun, Hua, Chen, Li, Yang and Gao.