Genetic Epidemiology of Caffeine and Cognitive Decline

项目摘要 脑卒中相关的认知能力下降是一种重要的人类疾病，其程度因人而异。这 变异可能是遗传和环境因素复杂的相互作用造成的。咖啡因是最 世界上最常见的行为活性物质，越来越多的文献指出， 前提是咖啡因可以提供一种安全、有效、容易获得和廉价的治疗剂 对抗认知能力下降然而，导致咖啡因代谢变化的因素可能与 咖啡因摄入量，并改变其与认知能力下降的关系。此外，咖啡因靶向基因， 可能影响认知能力下降的途径，从而有机会促进我们对 如果不考虑咖啡因代谢的变化，这种情况可能会被忽略。 博士科内利斯提出了一个培训和研究计划，这将有助于她成为一个独立的目标， 营养和认知能力下降系统流行病学研究者。获得以下方面的培训：i）认知 功能评估ii）认知衰退的流行病学和iii）认知衰退的神经病理学方面 和阿尔茨海默氏症，她与来自两个高度国际认可的导师团队密切合作， 致力于老龄化研究和从事培训活动，包括课程，一个著名的机构， 一对一和小组会议，研讨会和会议，观察和动手实践。 她将把她的训练应用于对遗传学联合效应的首次全面和高效的分析 和咖啡因对认知能力下降的影响咖啡因代谢率和咖啡因暴露的综合指数将被 用于流行病学荟萃分析框架，以检查基因与咖啡因摄入量的相互作用， 认知能力下降，并通过模拟SNP与咖啡因暴露的相互作用来发现这种情况的新位点 在全基因组范围内。 博士科内利斯的研究将提供关键的见解，咖啡因在减缓 认知能力下降，并有可能揭示这种情况下的新的生物学途径。结果 这项工作应该促进对认知障碍和开发新的行为的新的调查路线， 以及安全有效的治疗和预防的药理学途径。此外，经验和 从科内利斯博士的培训和研究计划的完成获得的知识将使她获得 R 01资金用于获取额外的系统级数据，以更详细地了解咖啡因或 其他饮食因素影响认知能力下降。 该行政补充将允许Cornelis博士完成其K 01培训和研究， 受到COVID-19疫情影响。用于营养数据管理的队列和研究人员有限 需要研究修改和更多的时间。COVID-19还扰乱了科内利斯博士的神经病理学培训 需要及时完成K 01分析。

PROJECT SUMMARY Age-associated cognitive decline is an important human condition that varies in extent among individuals. This variation likely arises from a complex interplay of genetic and environmental factors. Caffeine is the most commonly ingested behaviorally active substance in the world, and a growing body of literature points to the premise that caffeine may provide a safe, effective, readily available, and inexpensive therapeutic agent against cognitive decline. However, factors that contribute to variation in caffeine metabolism may interact with caffeine intake and modify its association with cognitive decline. Furthermore, caffeine targets genes and pathways potentially impacting cognitive decline and thus an opportunity to advancing our understanding of this condition may be missed if variation in caffeine metabolism is left unaccounted for. Dr. Cornelis proposes a training and research plan that will contribute to her goal to become an independent investigator of systems epidemiology of nutrition and cognitive decline. To acquire training in i) cognitive function assessment ii) epidemiology of cognitive decline and iii) neuropathological aspects of cognitive decline and Alzheimer's disease, she works closely with a team of internationally recognized mentors from two highly reputable institutes committed to aging research and engages in training activities including coursework, one- on-one and small group sessions, seminars and conferences, observation and hands-on practicum. She will apply her training to the first comprehensive and highly efficient analysis of the joint effects of genetics and caffeine on cognitive decline. Composite indices of caffeine metabolic rate and caffeine exposure will be used in an epidemiological meta-analytical framework to examine genecaffeine intake interactions and cognitive decline and to discover novel loci for this condition by modeling SNPcaffeine exposure interactions on a genome-wide scale. Dr. Cornelis's research will provide critical insights into the role that caffeine potentially plays in slowing cognitive decline and has potential to uncover novel biological pathways underlying this condition. Results of this work should foster new lines of investigation for cognitive impairment and for developing novel behavioral and pharmacological avenues for safe and effective treatment and prevention. Moreover, the experience and knowledge obtained from the completion of Dr. Cornelis's training and research plan will allow her to obtain R01 funding to acquire additional systems-level data for a more detailed mechanistic view of how caffeine or other dietary factors impact cognitive decline. This Administrative Supplement will allow Dr. Cornelis to complete her K01 training and research that was disrupted by COVID-19 shutdowns. Limited availability of cohorts and research staff for nutrition data curation required research revisions and more time. COVID-19 also disrupted the neuropathology training Dr. Cornelis needed to complete her K01 analyses in a timely manner.