Ganoderma lucidum is a traditional Chinese medicine used to treat Alzheimer's disease (AD), whose main active ingredient is polysaccharides. A heteropolysaccharide named GLPZ-1 was isolated from Ganoderma lucidum. GLPZ-1 (6.608 kDa) predominantly consisted of Glc and minor Gal. The results of GC-MS and NMR analyses indicated that the backbone of GLPZ-1 was mainly composed of 1,4-α-D-Glcp, 1,4,6-α-Glcp and a minor amount of 1,3,4-β-D-Glcp, which was substituted with complex side chains at C-6 of 1,4,6-α-D-Glcp and at C-3 of 1,3,4-β-D-Glcp. GLPZ-1 demonstrated a protective effect on AD rats by improving behavioral abnormalities, alleviating pathological damage and ameliorating levels of IL-6, IL-1β, TNF-α and Th17, which were associated with GLPZ-1 modulating the microbiota-gut-metabolomics of AD rats. GLPZ-1 regulated the gut microbiota in AD rats by increasing the abundance of Bacteroides, unclassified_Lachnospiraceae, Lactobacillus, Pediococcus, Oscillibacter, Lachnoclostridium and Bifidobacterium, while simultaneously reducing the abundance of Pseudomonas and Desulfovibrio. GLPZ-1 could regulate fecal metabolites in AD rats tending towards the normal levels. These regulated fecal metabolites belonged to fatty acid metabolism, cholesterol and bile acid metabolism, neurotransmitters and aromatic amino acid metabolism. These findings provide a preliminary research basis for the exploitation of GLPZ-1 as an effective drug to prevent and delay AD.