目的·分析探讨空腹血糖（fasting blood glucose，FBG）升高人群中导致认知功能恶化的影响因素和导致认知功能恶化风险变化的代谢线索。方法·从阿尔茨海默病神经影像学计划数据库中下载阿尔茨海默病队列数据，并筛选出具有FBG数据和随访数据的样本，获得其临床资料［包括年龄、性别、身体质量指数、教育程度、载脂蛋白E4（apolipoprotein E4，APOE4）基因型、人种］和代谢指标数据（包括氨基酸、脂肪酸、蛋白质等）。根据受试者的FBG水平和认知障碍阶段诊断，将其分为正常FBG并无/有认知功能恶化组、FBG升高并无/有认知功能恶化组。采用单因素分析、Cox比例风险回归模型、正交偏最小二乘判别分析、Spearman相关性分析对数据进行分析。结果·共纳入1 317例具有FBG数据且具有较为完整的临床资料与代谢物数据的受试者，其中FBG正常（>3.9 mmol/L且<6.1 mmol/L）共1 153例，FBG升高（≥6.1 mmol/L）共164例。FBG正常的受试者中，275例有认知功能恶化；FBG升高的受试者中，53例有认知功能恶化。基线人口统计学特征分析结果显示，正常FBG组和高FBG组在性别、人种上差异有统计学意义，无认知功能恶化组和有认知功能恶化组在年龄、性别、APOE4基因携带率上差异有统计学意义（均P<0.05）。Cox回归分析表明，认知功能恶化的主要促进因素依次为APOE4基因阳性、FBG升高和年龄增长（HR=2.22，HR=1.38，HR=1.02；均P<0.05）。不同FBG水平下无认知功能恶化和有恶化组的基线代谢指标，以及认知功能恶化前与认知功能恶化后的代谢指标的差异分析结果显示：在认知功能恶化人群中，高密度脂蛋白（high-density lipoproteins，HDL）携带的磷脂在总脂质中的比值显著升高；低密度脂蛋白（low-density lipoprotein，LDL）颗粒浓度及其携带的脂质含量在认知功能恶化后显著升高。相关性分析结果显示，在认知功能恶化人群中，缬氨酸、亮氨酸不仅与FBG水平显著相关，还与血浆磷酸化tau蛋白（phosphorylated tau，pTau）水平显著相关；HDL携带的胆固醇含量、磷脂与总脂质的比值与脑脊液pTau水平显著相关。结论·相较于FBG正常的人群，FBG升高人群认知功能恶化风险显著增加；且不同FBG水平下，无认知功能恶化人群和有认知功能恶化的人群以及认知恶化前与认知恶化后显著差异的代谢指标有所不同。总体而言，LDL及其携带的脂质、HDL携带的磷脂在认知功能恶化过程中呈上升趋势，且支链氨基酸中的缬氨酸与亮氨酸与pTau水平有显著相关性，提示这几个代谢指标在认知功能恶化过程中或许起重要作用。

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.