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.

神经退行性疾病转化失败的一个主要解释是，当临床特征变得不可逆转时，新药是在病程后期进行评估的。为了解决这一差距，我们对 21,051 名 17-85 岁的人进行了认知分析，他们是英格兰国家健康与护理研究生物资源研究所基因与认知队列的一部分。我们描述了该群体，呈现了认知轨迹并展示了潜在的效用。令人惊讶的是，当进行大规模研究时，APOE基因型对认知表现的影响可以忽略不计。不同的认知域具有不同的遗传结构，其中一个表示大脑区域特定的小胶质细胞激活，另一个表示糖原代谢。因此，支撑认知的分子和细胞机制与痴呆风险位点不同，提出了不同的目标来减缓与年龄相关的认知衰退。现在可以根据基因型和认知表型对参与者进行分层回忆，以进行神经退行性疾病和其他疾病的自然史和介入研究。