Aims: To analyze the effect of APOE epsilon 4 on fluid biomarkers and the correlations between blood molecules and CSF biomarkers in AD patients. Methods: This study enrolled 575 AD patients, 131 patients with non-AD dementia, and 112 cognitively normal (CN) participants, and AD patients were divided into APOE epsilon 4 carriers and non-carriers. Cerebrospinal fluid (CSF) biomarkers and blood-derived biomolecules were compared between AD and CN groups, between non-AD dementia and CN groups, as well as within APOE epsilon 4 subgroups of AD patients. Utilizing Spearman's correlation analysis and quantile regression analysis, the relationships between blood-derived biomolecules and CSF biomarkers were analyzed in APOE epsilon 4 carriers and non-carriers. Results: The levels of CSF biomarkers and blood molecules exhibited significant differences between the AD and CN groups, including A beta 42, t-tau, p-tau 181, high-density lipoprotein, low-density lipoprotein (LDL), and uric acid. In AD patients, APOE epsilon 4 carriers had increased levels of CSF t-tau, p-tau 181, and plasma LDL. In the correlation and regression analyses, the negative relationships between plasma TG and t-tau, between plasma TG and p-tau 181 levels, as well as the positive relationship between serum IgA and CSF A beta 42, were observed significantly in APOE epsilon 4+ AD groups, but not in APOE epsilon 4- AD group. Conclusion: APOE epsilon 4 is associated with accelerated progression of AD pathology. The blood-derived biomolecules correlated with CSF biomarkers in APOE epsilon 4 carriers are related to neuroinflammation and lipid metabolism, which may indicate the role of APOE epsilon 4 in AD pathophysiology and offer insights for diagnostic and therapeutic strategies for AD. Trial Registration identifier: NCT03653156