ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) belongs to the category of "forgetfulness" or "dementia" in traditional Chinese medicine, and is often caused by deficiency of five zang-viscera. Longan Aril (the aril of Dimocarpus longan Lour., LA) possesses properties beneficial for heart and spleen health, blood nourishment, and mind tranquility, suggesting its potential as a treatment for AD. This study aimed to investigate the therapeutic effects of Longan Aril polysaccharides (LAPs), a primary active constituent of LA, on lipopolysaccharides (LPS) and amyloid β-peptide (Aβ) induced immune tolerance in AD mice. Further, BV2 cells were employed to explore the mechanism of LAPs in improving immune tolerance. MATERIAL AND METHODS: LAPs were prepared by water extraction and alcohol precipitation. The monosaccharide composition was determined by high-performance liquid chromatography (HPLC). An AD mouse model of immune tolerance was established by intraperitoneal (i.p) injection of LPS combined with intracerebroventricular (ICV) injection of Aβ RESULTS: LAPs contained five monosaccharides. LAPs improved cognitive function and increased the number of Nissl bodies, lactate secretion, the IL-10 content, the relative fluorescence intensity of the IBA1 and AXL proteins, and the protein expression levels of AXL, Mertk, Glut1, HK2, PI3K, p-Akt/Akt, p-mTOR/mTOR and HIF-1α of immune-tolerant AD mice. LAPs also reduced the TNF-α content, and the protein expression level of CD68 in immune-tolerant AD mice. In vitro, LAPs elevated the IL-10 content and protein expression levels of PI3K, Akt, p-Akt, and HIF-1α, while reducing lactate secretion and the TNF-α content in immune-tolerant BV2 cells. LAPs promoted the phagocytic activity of BV2 cells, and their effects are completely inhibited by 2-DG and partially inhibited by BAY and Rapa. CONCLUSIONS: LAPs can enhance the cognitive abilities of immune-tolerant AD mice and diminish their pathological damage. The mechanism involves the regulation of glycolysis and the PI3K/Akt/mTOR/HIF-1α signaling pathway to promote microglial immune phagocytosis.