长寿成年人的认知障碍：一项全基因组关联研究、多基因风险评分模型及载脂蛋白E蛋白的分子建模
Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein.
作者信息
Kashtanova D A, Mamchur A A, Dzhumaniyazova I H, Ivanov M V, Erema V V, Zelenova E A, Yakovchik A Y, Gusakova M S, Rumyantseva A M, Terekhov M V, Matkava L R, Akopyan A A, Strazhesko I D, Yudin V S, Makarov V V, Kraevoy S A, Tkacheva O N, Yudin S M
机构信息
Federal State Budgetary Institution "Centre for Strategic Planning and Management of Biomedical Health Risks", Federal Medical Biological Agency, Moscow, Russia.
Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.
出版信息
Front Aging Neurosci. 2023 Oct 26;15:1273825. doi: 10.3389/fnagi.2023.1273825. eCollection 2023.
BACKGROUND
Cognitive impairment is an irreversible, aging-associated condition that robs people of their independence. The purpose of this study was to investigate possible causes of this condition and propose preventive options.
METHODS
We assessed cognitive status in long-living adults aged 90+ ( = 2,559) and performed a genome wide association study using two sets of variables: Mini-Mental State Examination scores as a continuous variable (linear regression) and cognitive status as a binary variable (> 24, no cognitive impairment; <10, impairment) (logistic regression).
RESULTS
Both variations yielded the same polymorphisms, including a well-known marker of dementia, rs429358in the APOE gene. Molecular dynamics simulations showed that this polymorphism leads to changes in the structure of alpha helices and the mobility of the lipid-binding domain in the APOE protein.
CONCLUSION
These changes, along with higher LDL and total cholesterol levels, could be the mechanism underlying the development of cognitive impairment in older adults. However, this polymorphism is not the only determining factor in cognitive impairment. The polygenic risk score model included 45 polymorphisms (ROC AUC 69%), further confirming the multifactorial nature of this condition. Our findings, particularly the results of PRS modeling, could contribute to the development of early detection strategies for predisposition to cognitive impairment in older adults.
背景
认知障碍是一种不可逆转的、与衰老相关的状况，会剥夺人们的独立性。本研究的目的是调查这种状况的可能原因并提出预防方案。
方法
我们评估了90岁及以上的长寿成年人（n = 2559）的认知状态，并使用两组变量进行了全基因组关联研究：作为连续变量的简易精神状态检查表得分（线性回归）以及作为二元变量的认知状态（> 24，无认知障碍；< 10，有障碍）（逻辑回归）。
结果
两种变异产生了相同的多态性，包括载脂蛋白E（APOE）基因中一个著名的痴呆标记rs429358。分子动力学模拟表明，这种多态性导致了α螺旋结构的变化以及APOE蛋白中脂质结合域的流动性变化。
结论
这些变化，连同较高的低密度脂蛋白和总胆固醇水平，可能是老年人认知障碍发展的潜在机制。然而，这种多态性并不是认知障碍的唯一决定因素。多基因风险评分模型包含45种多态性（受试者工作特征曲线下面积为69%），进一步证实了这种状况的多因素性质。我们的研究结果，特别是多基因风险评分建模的结果，可能有助于制定老年人认知障碍易感性的早期检测策略。
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