The significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian Randomization approaches to investigate the causal relationship between classical risk factors and primary CAD in different age groups. A Mendelian Randomization study was conducted in European-ethnicity individuals from the UK Biobank population. Analyses were performed using data of 22,313 CAD cases (71.6% men) and 407,920 controls (44.5% men). Using logistic regression analyses, we investigated the associations between standardized genetic risk score and primary CAD stratified by age of diagnosis. In addition, feature importance and model accuracy were assessed in different age groups to evaluate predictive power of the genetic risk scores with increasing age. We found age-dependent associations for all classical CAD risk factors. Notably, body mass index (OR 1.22 diagnosis < 50 years; OR 1.02 diagnosis > 70 years), blood pressure (OR 1.12 < 50 years; OR 1.04 > 70 years), LDL cholesterol (OR 1.16 < 50 years; OR 1.02 > 70 years), and triglyceride levels (OR 1.11 < 50 years; 1.04 > 70 years). In line with the Mendelian Randomization analyses, model accuracy and feature importance of the classical risk factors decreased with increasing age of diagnosis. Causal determinants for primary CAD are age dependent with classical CAD risk factors attenuating in relation with primary CAD with increasing age. These results question the need for (some) currently applied cardiovascular disease risk reducing interventions at older age.

由于潜在疾病病理学可能发生变化，冠状动脉疾病 (CAD) 中经典危险因素的意义在老年人中仍不清楚。因此，我们采用孟德尔随机化方法来研究不同年龄组中经典危险因素与原发性 CAD 之间的因果关系。一项孟德尔随机化研究是在来自英国生物银行人群的欧洲种族个体中进行的。使用 22,313 例 CAD 病例（71.6% 男性）和 407,920 例对照（44.5% 男性）的数据进行分析。使用逻辑回归分析，我们调查了标准化遗传风险评分与按诊断年龄分层的原发性 CAD 之间的关联。此外，在不同年龄组中评估特征重要性和模型准确性，以评估遗传风险评分随年龄增长的预测能力。我们发现了所有经典 CAD 风险因素的年龄依赖性关联。值得注意的是，体重指数（OR 1.22 诊断 < 50 岁；OR 1.02 诊断 > 70 岁）、血压（OR 1.12 < 50 岁；OR 1.04 > 70 岁）、低密度脂蛋白胆固醇（OR 1.16 < 50 岁；OR 1.02 > 70年）和甘油三酯水平（OR 1.11 < 50 岁；1.04 > 70 岁）。根据孟德尔随机化分析，经典风险因素的模型准确性和特征重要性随着诊断年龄的增加而降低。原发性 CAD 的因果决定因素是年龄依赖性的，与原发性 CAD 相关的经典 CAD 风险因素随着年龄的增加而减弱。