From the Department of Epidemiology and Biostatistics (E.L.F., S.C.Z., M.C., K.S., T.J.H., N.R., M.M.G.), University of California, San Francisco; Kaiser Permanente Division of Research (C.J., V.C., T.J.M., P.G., C.A.S.), Oakland; Institute for Human Genetics (A.O.-O., N.R.); Department of Clinical Pharmacy (A.O.-O.), University of California, San Francisco; Department of Public Health Sciences (R.A.W.), University of California, Davis; and Departments of Pediatrics and Medicine (R.M.K.), University of California, San Francisco. K.S. is currently affiliated with the VA Boston Healthcare System, MA. T.J.H. is currently affiliated with the Department of Epidemiology and Biostatistics, University of California, San Francisco, and the Institute for Human Genetics, University of California, San Francisco. P.G. is currently affiliated with the Kaiser Permanente Division of Research, Oakland, CA, and the Department of Epidemiology and Biostatistics, University of California, San Francisco. N.R. is currently affiliated with the Department of Epidemiology and Biostatistics, the Institute for Human Genetics, University of California, San Francisco, and the Kaiser Permanente Division of Research, Oakland, CA. M.M.G. is currently affiliated with the Department of Epidemiology, Boston University School of Public Health, MA.
Neurology. 2023 Nov 21;101(21):e2172-e2184. doi: 10.1212/WNL.0000000000207876. Epub 2023 Oct 4.
BACKGROUND AND OBJECTIVES: The associations of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) with dementia risk in later life may be complex, and few studies have sufficient data to model nonlinearities or adequately adjust for statin use. We evaluated the observational associations of HDL-C and LDL-C with incident dementia in a large and well-characterized cohort with linked survey and electronic health record (EHR) data. METHODS: Kaiser Permanente Northern California health plan members aged 55 years and older who completed a health behavior survey between 2002 and 2007, had no history of dementia before the survey, and had laboratory measurements of cholesterol within 2 years after survey completion were followed up through December 2020 for incident dementia (Alzheimer disease-related dementia [ADRD]; Alzheimer disease, vascular dementia, and/or nonspecific dementia) based on ICD-9 or ICD-10 codes in EHRs. We used Cox models for incident dementia with follow-up time beginning 2 years postsurvey (after cholesterol measurement) and censoring at end of membership, death, or end of study period. We evaluated nonlinearities using B-splines, adjusted for demographic, clinical, and survey confounders, and tested for effect modification by baseline age or prior statin use. RESULTS: A total of 184,367 participants [mean age at survey = 69.5 years, mean HDL-C = 53.7 mg/dL (SD = 15.0), mean LDL-C = 108 mg/dL (SD = 30.6)] were included. Higher and lower HDL-C values were associated with elevated ADRD risk compared with the middle quantile: HDL-C in the lowest quintile was associated with an HR of 1.07 (95% CI 1.03-1.11), and HDL-C in the highest quintile was associated with an HR of 1.15 (95% CI 1.11-1.20). LDL-C was not associated with dementia risk overall, but statin use qualitatively modified the association. Higher LDL-C was associated with a slightly greater risk of ADRD for statin users (53% of the sample, HR per 10 mg/dL increase = 1.01, 95% CI 1.01-1.02) and a lower risk for nonusers (HR per 10 mg/dL increase = 0.98; 95% CI 0.97-0.99). There was evidence for effect modification by age with linear HDL-C ( = 0.003) but not LDL-C ( = 0.59). DISCUSSION: Both low and high levels of HDL-C were associated with elevated dementia risk. The association between LDL-C and dementia risk was modest.
背景和目的：高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）与晚年痴呆风险的关联可能很复杂，而且很少有研究有足够的数据来模拟非线性，或充分调整他汀类药物的使用。我们在一个具有链接调查和电子健康记录（EHR）数据的大型、特征良好的队列中，评估了 HDL-C 和 LDL-C 与痴呆症发病风险的观察性关联。
方法：Kaiser Permanente 北加利福尼亚健康计划成员，年龄在 55 岁及以上，在 2002 年至 2007 年期间完成了健康行为调查，在调查前没有痴呆症病史，并且在调查完成后 2 年内有胆固醇实验室测量值，通过 EHR 中的 ICD-9 或 ICD-10 代码，随访至 2020 年 12 月，以确定痴呆症（阿尔茨海默病相关痴呆症[ADRD]；阿尔茨海默病、血管性痴呆和/或非特定痴呆）的发病情况。我们使用 Cox 模型来分析发病痴呆症的风险，随访时间从调查后 2 年开始（在胆固醇测量后），并在会员资格结束、死亡或研究期结束时进行删失。我们使用 B-样条评估非线性，调整了人口统计学、临床和调查混杂因素，并测试了基线年龄或既往他汀类药物使用的效应修饰作用。
结果：共有 184367 名参与者（调查时的平均年龄为 69.5 岁，平均 HDL-C 为 53.7mg/dL[标准差（SD）为 15.0]，平均 LDL-C 为 108mg/dL[SD 为 30.6]）被纳入研究。与中间五分位数相比，较高和较低的 HDL-C 值与 ADRD 风险升高相关：最低五分位数的 HDL-C 与 HR 为 1.07（95%CI 1.03-1.11），最高五分位数的 HDL-C 与 HR 为 1.15（95%CI 1.11-1.20）。LDL-C 与痴呆症风险总体上无关联，但他汀类药物的使用对该关联有定性修饰作用。对于他汀类药物使用者，较高的 LDL-C 与 ADRD 风险略有增加（53%的样本，每增加 10mg/dL 的 HR=1.01，95%CI 1.01-1.02），而非使用者的风险降低（每增加 10mg/dL 的 HR=0.98；95%CI 0.97-0.99）。HDL-C 与年龄之间存在线性效应修饰（ = 0.003），但 LDL-C 则没有（ = 0.59）。
讨论：低和高 HDL-C 水平均与痴呆风险升高相关。LDL-C 与痴呆症风险的关联较弱。
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