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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02960-5

摘要内容如下：

神经退行性疾病转化失败的一个主要解释是，在病程晚期，当临床特征变得不可逆时，才对新药进行评估。在这里，为了解决这一差距，我们对21，051名年龄在17-85岁之间的人进行了认知分析，作为英格兰国家卫生和保健研究所生物资源的基因和认知队列的一部分。我们描述了队列，提出了认知轨迹，并展示了潜在的效用。令人惊讶的是，当大规模研究时，ApoE基因型对认知表现的影响可以忽略不计。不同的认知领域具有不同的遗传结构，其中一个与小胶质细胞的脑区特异性激活有关，另一个与糖原代谢有关。因此，支撑认知的分子和细胞机制不同于痴呆风险位点，呈现出不同的目标来减缓与年龄相关的认知衰退。参与者现在可以根据基因型和认知表型进行分层，用于神经退行性疾病和其他疾病的自然史和干预性研究。

英文原文如下：

Abstracts

A leading explanation for translational failure in neurodegenerative disease is that new drugs are evaluated late in the disease course when clinical features have become irreversible. Here, to address this gap, we cognitively profiled 21,051 people aged 17-85 years as part of the Genes and Cognition cohort within the National Institute for Health and Care Research BioResource across England. We describe the cohort, present cognitive trajectories and show the potential utility. Surprisingly, when studied at scale, the APOE genotype had negligible impact on cognitive performance. Different cognitive domains had distinct genetic architectures, with one indicating brain region-specific activation of microglia and another with glycogen metabolism. Thus, the molecular and cellular mechanisms underpinning cognition are distinct from dementia risk loci, presenting different targets to slow down age-related cognitive decline. Participants can now be recalled stratified by genotype and cognitive phenotype for natural history and interventional studies of neurodegenerative and other disorders.

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