Objective ·To analyze and explore the influencing factors that lead to cognitive deterioration in individuals with elevated fasting blood glucose (FBG) and the metabolic clues associated with changes in the risk of cognitive deterioration. Methods ·Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were downloaded, and the samples with FBG and follow-up data were selected from the database. Clinical information, including age, gender, body mass index, education years,apolipoprotein E4 (APOE4) genotype and race, and corresponding metabolic indicator data, including amino acids, fatty acids, proteins and others were obtained. Based on the FBG levels and diagnosis of cognitive impairment stages in Alzheimer's disease, the subjects were categorized into four groups: normal FBG without/with cognitive deterioration, and elevated FBG without/with cognitive deterioration. The univariate analysis method, the Cox proportional hazards model, orthogonal projections to latent structures discriminant analysis (OPLSDA), and Spearman correlation analysis were employed for data analysis. Results ·A total of 1 317 subjects were included, among which 1 153 had normal FBG level (>3.9 mmol/L and <6.1 mmol/L) and 164 had elevated FBG level (≥6.1 mmol/L). In the normal FBG group, 275 subjects showed cognitive deterioration, while in the elevated FBG group, 53 subjects showed cognitive deterioration. Univariate analysis revealed significant differences in gender and race between the normal FBG and elevated FBG group, and significant differences in age, gender, and APOE4 genotype between the groups with and without cognitive deterioration (all P<0.05). Cox regression analysis indicated that primary influencing factors for cognitive deterioration were APOE4 positivity, elevated FBG, and increasing age in order (HR=2.22,HR=1.38,HR=1.02; all P<0.05). In the analysis of baseline metabolic indicators in the groups without and with cognitive deterioration, as well as metabolic indicators before and after cognitive deterioration at different FBG levels, the results of the analysis of variance revealed that in the cognitively deteriorated population, the ratio of phospholipids carried by high-density lipoproteins (HDL) to total lipids was significantly higher; low-density lipoprotein (LDL) particle concentration and the lipids carried by LDL were significantly higher after cognitive deterioration. Correlation analysis showed that valine and leucine were significantly correlated not only with FBG level but also with phosphorylated tau (pTau) level in the plasma in the cognitively deteriorated population. Cholesterol and the ratio of phospholipids to total lipids carried by HDL were significantly correlated with pTau levels in cerebrospinal fluid (CSF). Conclusion ·Compared to the individuals with normal FBG level, those with high FBG level have a significantly higher risk of cognitive deterioration. Additionally, different metabolic indicators show significant differences between the groups without and with cognitive deterioration, as well as metabolic indicators before and after cognitive deterioration at different FBG levels. Overall, LDL and its lipid content, and HDL-carried phospholipids show an increasing trend during cognitive deterioration, and the branched-chain amino acids valine and leucine are significantly correlated with pTau levels in CSF and plasma, suggesting that these metabolic markers may play an important role in cognitive deterioration.