背景与目的

近年来，我国人口老龄化进程加快，痴呆等认知功能疾病的患病率逐年升高，预防认知功能障碍发生可以有效延缓痴呆进展。血脂异常与心血管疾病和认知功能障碍密切相关，临床实践中常通过控制血脂水平预防心血管疾病，但尚不清楚较低的血脂水平是否对认知功能产生不利影响。考虑到血脂水平在全生命期的波动变化，单次测量结果无法准确评价血脂对认知功能的长期作用。同时，血脂水平和认知功能与遗传因素密切相关，遗传因素是否在血脂对认知功能的相关影响中起到修饰作用，有待深入探讨。

为此，本研究基于中国人群队列随访数据，评估了总胆固醇（total cholesterol，TC）、甘油三酯（triglyceride，TG）、低密度脂蛋白胆固醇（low-density lipoprotein cholesterol，LDL-C）和高密度脂蛋白胆固醇（high-density lipoprotein cholesterol，HDL-C）累积暴露水平与认知功能障碍的关系。根据研究对象的血脂遗传风险以及认知功能相关基因，探讨遗传因素和血脂累积暴露对认知功能障碍的潜在交互作用。

方法

基于中国动脉粥样硬化性心血管疾病风险预测队列，纳入2018-2019年开展认知功能随访调查的9,542名个体。认知功能评估使用简易精神状态检查量表（Mini-Mental State Examination，MMSE），结合教育程度和量表得分，将未受教育者≤17分、小学学历者≤20分、中学及以上学历者≤24分定义为认知功能障碍。血脂累积暴露定义为基线调查至2012-2015年随访期间血脂测量水平的时间加权平均值。基于东亚人群全基因组关联研究，筛选与血脂水平显著关联（P < 5×10^-8）的126个血脂相关SNP，构建4种血脂的遗传风险评分（polygenic risk score，PRS）并根据人群分布定义低（前20%）、中（20-80%）和高（后20%）血脂遗传风险组。基于连锁不平衡原理，使用rs769449和rs445925定义与研究对象认知功能相关的APOE基因型，并根据APOE等位基因组合，将研究对象划分为APOE ε2携带组、APOE ε3/ε3组以及APOE ε4携带组。采用多因素Logistic回归模型计算血脂累积暴露水平和血脂PRS每降低一个标准差（standard deviation，SD）时，认知功能障碍的比值比（odds ratio，OR）和95%置信区间（confidence interval，CI）。使用限制性立方样条检验血脂累积暴露水平与认知功能障碍之间是否存在非线性关联。采用Spearman相关系数评估4种血脂PRS与相应血脂累积暴露水平的相关性。根据研究对象的血脂遗传风险和APOE基因型，进一步探讨不同遗传特征人群血脂累积暴露水平与认知功能障碍的关联，并评估遗传因素与血脂累积暴露之间是否存在交互作用。

结果

研究对象的基线中位年龄（四分位数间距）为66.76（62.27，70.58）岁，MMSE平均得分（SD）为25.12（6.57）分。研究对象TC和LDL-C累积暴露的平均值（SD）分别为186.28（30.91）mg/dL和108.01（26.19）mg/dL，2012-2015年随访时TC和LDL-C水平的平均值（SD）分别为189.72（38.70）mg/dL和110.72（33.39）mg/dL。经过中位随访时间5.75年，1,435名个体（15.04%）被定义为认知功能障碍。调整协变量后，TC和LDL-C累积暴露水平每降低一个标准差，认知功能障碍的OR（95%CI）均为1.10（1.02-1.19），未观察到TG和HDL-C与认知功能障碍存在显著关联。

血脂PRS与相应血脂累积暴露水平显著相关（P<0.001），PRS_TC与TC累积暴露水平的Spearman相关系数和解释度分别为0.233和5.62%，PRS_LDL-C与LDL-C累积暴露水平的Spearman相关系数和解释度分别为0.248和6.21%。调整协变量后，未观察到PRS_TC和PRS_LDL-C与认知功能障碍之间存在显著关联。TC和LDL-C遗传风险与相应血脂累积暴露之间未表现出对认知功能障碍的显著交互作用（P_交互作用分别为0.548和0.541）。

与APOE ε3/ε3人群相比，APOE ε4携带者认知功能障碍的OR（95%CI）为1.08（0.89-1.31），调整协变量后未达到统计学显著性。APOE ε4与TC、LDL-C累积暴露对认知功能障碍的影响未表现出显著的交互作用（P_交互作用分别为0.575和0.838）。进一步按照携带APOE ε4与否分层分析，APOE ε4携带者TC和LDL-C累积暴露水平每降低一个标准差，认知功能障碍的OR（95%CI）分别为1.24（1.02-1.50）和1.20（0.99-1.45），与LDL-C的关联表现为边缘显著；相反，非APOE ε4携带者TC和LDL-C累积暴露水平每降低一个标准差，认知功能障碍风险均未观察到显著增加（OR_TC：1.07，95%CI：0.99-1.17；OR_LDL-C：1.08，95%CI：1.00-1.18）。

结论

本研究基于中国人群队列，发现较低的TC和LDL-C累积暴露水平与认知功能障碍相关。个体TC和LDL-C的先天遗传风险未对血脂水平与认知功能的关联产生效应修饰作用；而作为认知功能相关的遗传因素，APOE基因对该关联存在潜在影响，即APOE ε4携带者呈现出更强的关联强度。本研究提示评估血脂累积水平对认知功能的影响时，需综合考虑个体APOE 遗传信息，为认知功能障碍精准预防提供了潜在科学证据。

Background and Objectives

In recent years, the aging process of the Chinese population has accelerated, and the prevalence of cognitive disorders such as dementia has increased year by year. Preventing cognitive impairment can effectively delay the progression of dementia. Dyslipidemia is closely associated with related to both cardiovascular disease and cognitive impairment. In clinical practice, lipid-lowering therapy is commonly used to prevent cardiovascular diseases; however, it remains unclear whether relatively low lipid levels have adverse effects on cognitive function. Considering the dynamic fluctuations of lipid levels across the lifespan, a single-time-point measurement may not accurately reflect the long-term impact of lipids on cognitive function. Moreover, both lipid levels and cognitive function are closely influenced by genetic factors. Whether genetic predisposition modulates the association between lipid exposure and cognitive outcomes remains to be further elucidated.

Therefore, based on longitudinal cohort data from the Chinese population, this study aimed to evaluate the association between cumulative exposure to total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) and the risk of cognitive impairment. In addition, we investigated the potential modifying effect of genetic factors, such as lipid-related polygenic risk scores and APOE genotype, on the association between long-term lipid exposure and cognitive impairment.

Methods

This study was based on the Prediction for Atherosclerotic Cardiovascular Disease Risk in China Project and included 9,542 participants who completed cognitive function assessments between 2018 and 2019 follow-up. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Based on educational attainment and MMSE scores, cognitive impairment was defined as MMSE ≤17 for illiterate individuals, ≤20 for primary school education, and ≤24 for middle school education or above. Cumulative lipid exposure was defined as the time-weighted average of lipid measurements from baseline to the 2012-2015 follow-up. Using genome-wide association studies (GWAS) from East Asian populations, we identified 126 SNPs significantly associated with lipid levels (P < 5×10^-8) to construct polygenic risk scores (PRSs) for lipid traits. Participants were classified into low (bottom 20%), intermediate (20-80%), and high (top 20%) genetic risk groups according to PRS distribution.

Based on the principle of linkage disequilibrium, APOE genotypes associated with cognitive function were determined using rs769449 and rs445925. Participants were then categorized into three groups according to their APOE allele combinations: APOE ε2 carriers, APOE ε3/ε3 homozygotes, and APOE ε4 carriers. Continuous variables were described as mean ± standard deviation (SD) or median with interquartile range (IQR), and categorical variables as frequency and percentage. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for cognitive impairment per one-standard-deviation decrease in cumulative lipid levels. Restricted cubic splines were used to assess the potential nonlinear relationships between cumulative lipid exposure and the risk of cognitive impairment. Spearman correlation coefficients were calculated to evaluate the associations between four types of lipid PRSs and their corresponding cumulative lipid exposure levels. Stratified analyses were conducted by lipid genetic risk and APOE genotype to further examine the association between cumulative lipid exposure and cognitive impairment in different genetic subgroups, and to assess potential interactions between genetic risk and lipid levels.

Results

The median baseline age of the participants (IQR) was 66.76 (62.27, 70.58) years, and the mean MMSE score (SD) was 25.12 (6.57) points. The mean (SD) cumulative exposures to total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were 186.28 (30.91) mg/dL and 108.01 (26.19) mg/dL, respectively. At follow-up (2012–2015), the average levels increased slightly to 189.72 (38.70) mg/dL for TC and 110.72 (33.39) mg/dL for LDL-C. During a median follow-up of 5.75 years, 1,435 individuals (15.04%) were identified with cognitive impairment. After adjusting for covariates, each SD decrease in cumulative TC and LDL-C exposure was associated with 10% higher odds of cognitive impairment (OR for both: 1.10, 95% CI: 1.02-1.19). No significant associations were observed between TG or HDL-C and cognitive impairment.

Lipid PRSs were significantly correlated with corresponding cumulative lipid exposure levels (P < 0.001). The Spearman correlation coefficients and the proportion of variance explained were 0.233 and 5.62% for PRS_TC with cumulative TC exposure, and 0.248 and 6.21% for PRS_LDL-C with cumulative LDL-C exposure. However, after adjusting for covariates, neither PRS_TC nor PRS_LDL-C was significantly associated with cognitive impairment. No significant interactions were observed between lipid-related genetic risk and cumulative lipid exposure to cognitive impairment (P for interaction=0.548 for TC and 0.541 for LDL-C, respectively).

Compared with individuals carrying the APOE ε3/ε3 genotype, APOE ε4 carriers showed a higher odds of cognitive impairment compared to those with the ε3/ε3 genotype (OR: 1.08, 95% CI: 0.89-1.31). However, the association was not statistically significant after adjusting for covariates. No significant interactions were observed between APOE ε4 status and cumulative TC or LDL-C exposure on cognitive impairment risk (P for interaction=0.575 and 0.838, respectively). In stratified analyses, each SD decrease in cumulative TC and LDL-C exposure among APOE ε4 carriers was associated with a 24% (OR: 1.24, 95% CI: 1.05-1.50) and 20% (OR: 1.20, 95% CI: 0.99-1.45) increased odds of cognitive impairment, respectively, with the association for LDL-C being marginally significant. In contrast, among non-carriers of APOE ε4, no significant associations were observed between cumulative TC or LDL-C exposure and cognitive impairment (OR_TC: 1.07, 95% CI: 0.99-1.17; OR_LDL-C: 1.08, 95% CI: 1.00-1.18).

Conclusion

Based on the Chinese population-based cohort, this study found that lower cumulative exposure to TC and LDL-C was associated with an increased risk of cognitive impairment. Inherited polygenic risk for TC and LDL-C did not modify the association between lipid levels and cognitive function. However, as a genetic factor directly associated with cognitive function, the APOE ε4 allele appeared to influence this association, with stronger effect estimates observed in individuals carrying the ε4 allele. These findings highlight the importance of incorporating individual APOE genetic information when evaluating the impact of long-term lipid exposure on cognitive function and provide potential scientific evidence for the precision prevention of cognitive impairment.