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.

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.

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 (p = 0.003) but not LDL-C (p = 0.59).

Both low and high levels of HDL-C were associated with elevated dementia risk. The association between LDL-C and dementia risk was modest.

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，很少有研究拥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。我们通过关联调查和电子健康记录 (EHR) 数据，在一个大型且特征明确的队列中评估了 HDL-C 和 LDL-C 与痴呆症的观察关联。

Kaiser Permanente 北加州健康计划会员年龄在 55 岁及以上，在 2002 年至 2007 年间完成了健康行为调查，调查前没有痴呆病史，并在调查完成后 2 年内进行了实验室胆固醇测量，随访至 2020 年 12 月根据 EHR 中的 ICD-9 或 ICD-10 代码，针对突发性痴呆（阿尔茨海默病相关痴呆 [ADRD]；阿尔茨海默病、血管性痴呆和/或非特异性痴呆）进行诊断。我们使用 Cox 模型来处理痴呆事件，随访时间从调查后 2 年开始（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审查。我们使用 B 样条曲线评估非线性，根据人口统计、临床和调查混杂因素进行调整，并测试基线年龄或之前使用他汀类药物的效果修正。

共有 184,367 名参与者[调查时平均年龄 = 69.5 岁，平均 HDL-C = 53.7 mg/dL (SD = 15.0)，平均 LDL-C = 108 mg/dL (SD = 30.6)]。与中间分位数相比，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) 相关，最高五分位数的 HDL-C 与 HR 相关。与 HR 1.15 相关（95% CI 1.11–1.20）。总体而言，LDL-C 与痴呆风险无关，但他汀类药物的使用定性地改变了这种关联。对于他汀类药物使用者来说，较高的 LDL-C 与 ADRD 风险稍高相关（53% 的样本，HR 每 10 mg/dL 增加 = 1.01，95% CI 1.01–1.02），而对于非使用者来说，较高的 ADRD 风险较低（HR 每 10 mg/dL 增加 = 1.01，95% CI 1.01–1.02）。 mg/dL 增加 = 0.98；95% CI 0.97–0.99）。有证据表明，线性 HDL-C ( p = 0.003)会影响年龄的效应，但 LDL-C 则不会 ( p = 0.59)。

HDL-C 水平低和高都与痴呆风险升高相关。LDL-C 与痴呆风险之间的关联不大。