Abstract: Objective To investigate the effect of remote ischemic conditioning (RIC) on cognitive function and myelination in five familial Alzheimer's disease (AD) gene mutation (5xFAD) mice through regulation of the phosphoinositide 3-kinase (PI3K)/serine/threonine kinase (AKT) signaling pathway.Methods 5xFAD mice were selected as an AD model and divided into three groups: wild-type (WT), 5xFAD, and RIC-5xFAD. Mice in the RIC-5xFAD group received RIC intervention, twice per day, for 28 consecutive days. At the end of the experiment, cognitive function was assessed by the Morris water maze test. Brain blood flow perfusion was measured by laser Doppler flowmetry (LDF). Myelin basic protein (MBP) levels in the hippocampus were detected by immunofluorescence and Western blot. The expression of key proteins in the PI3K/AKT signaling pathway was analyzed.Results Compared with the 5xFAD group, the RIC-5xFAD group showed significant improvement in the Morris water maze test (P<0.05). LDF results indicated that RIC significantly increased brain blood flow perfusion in 5xFAD mice (P<0.05). Immunofluorescence and Western blot analysis showed significant increases in hippocampal MBP levels and phosphorylation of PI3K and AKT in the RIC group (P<0.05).Conclusions RIC improves cognitive function and myelin integrity in 5xFAD mice by increasing brain blood flow perfusion and activating the PI3K/AKT signaling pathway, thereby significantly slowing the pathological progression of AD.