Understanding genetic influences on Alzheimer's disease (AD) may improve early identification. AD polygenic risk scores (AD-PRSs) are associated with increased odds of AD and mild cognitive impairment (MCI). Additional sources of genetic risk may also contribute to disease outcomes. Coronary artery disease (CAD) is a risk factor for AD, interacts with AD pathology, and is also heritable. We showed that incidence-based and prevalence-based CAD-PRSs moderate the association between the AD-PRS and MCI, but in opposing directions. Higher incidence-based CAD-PRSs interacted with the AD-PRS to further increase MCI risk. Conversely, the AD-PRS was predictive of MCI when prevalence-based CAD-PRSs were low. The latter finding is likely due to prevalent CAD cases being biased toward longer postevent survival times, perhaps selecting for protective loci that offset AD risk. These results demonstrate (1) the importance of examining multiple PRSs and their interactions; (2) how genetic risk for one disease can modify the impact of genetic risk for another; and (3) the importance of considering ascertainment procedures of GWAS used for genetic risk prediction.

中文翻译：

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冠心病的遗传风险改变了阿尔茨海默氏症遗传风险对轻度认知障碍的影响

了解遗传对阿尔茨海默病 (AD) 的影响可能会改善早期识别。AD 多基因风险评分 (AD-PRS) 与 AD 和轻度认知障碍 (MCI) 的几率增加有关。遗传风险的其他来源也可能导致疾病结果。冠状动脉疾病 (CAD) 是 AD 的危险因素，与 AD 病理学相互作用，并且也是可遗传的。我们表明，基于发病率和基于患病率的 CAD-PRS 缓和了 AD-PRS 和 MCI 之间的关联，但方向相反。基于较高发病率的 CAD-PRS 与 AD-PRS 相互作用，进一步增加 MCI 风险。相反，当基于患病率的 CAD-PRS 较低时，AD-PRS 可预测 MCI。后一个发现可能是由于普遍的 CAD 病例偏向于更长的事件后生存时间，也许选择可以抵消 AD 风险的保护性位点。这些结果表明 (1) 检查多个 PRS 及其相互作用的重要性；(2) 一种疾病的遗传风险如何改变遗传风险对另一种疾病的影响；(3) 考虑用于遗传风险预测的 GWAS 确定程序的重要性。