Green Rebecca, Lord Jodie, Xu Jin, Maddock Jane, Kim Min, Dobson Richard, Legido-Quigley Cristina, Wong Andrew, Richards Marcus, Proitsi Petroula
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
MRC Unit for Lifelong Health & Ageing at UCL, University College London, London, UK.
Brain Commun. 2021 Dec 15;4(1):fcab291. doi: 10.1093/braincomms/fcab291. eCollection 2022.
Investigating associations between metabolites and late midlife cognitive function could reveal potential markers and mechanisms relevant to early dementia. Here, we systematically explored the metabolic correlates of cognitive outcomes measured across the seventh decade of life, while untangling influencing life course factors. Using levels of 1019 metabolites profiled by liquid chromatography-mass spectrometry (age 60-64), we evaluated relationships between metabolites and cognitive outcomes in the British 1946 Birth Cohort ( = 1740). We additionally conducted pathway and network analyses to allow for greater insight into potential mechanisms, and sequentially adjusted for life course factors across four models, including sex and blood collection (Model 1), Model 1 + body mass index and lipid medication (Model 2), Model 2 + social factors and childhood cognition (Model 3) and Model 3 + lifestyle influences (Model 4). After adjusting for multiple tests, 155 metabolites, 10 pathways and 5 network modules were associated with cognitive outcomes. Of the 155, 35 metabolites were highly connected in their network module (termed 'hub' metabolites), presenting as promising marker candidates. Notably, we report relationships between a module comprised of acylcarnitines and processing speed which remained robust to life course adjustment, revealing palmitoylcarnitine (C16) as a hub (Model 4: = -0.10, 95% confidence interval = -0.15 to -0.052, = 5.99 × 10). Most associations were sensitive to adjustment for social factors and childhood cognition; in the final model, four metabolites remained after multiple testing correction, and 80 at < 0.05. Two modules demonstrated associations that were partly or largely attenuated by life course factors: one enriched in modified nucleosides and amino acids (overall attenuation = 39.2-55.5%), and another in vitamin A and C metabolites (overall attenuation = 68.6-92.6%). Our other findings, including a module enriched in sphingolipid pathways, were entirely explained by life course factors, particularly childhood cognition and education. Using a large birth cohort study with information across the life course, we highlighted potential metabolic mechanisms associated with cognitive function in late midlife, suggesting marker candidates and life course relationships for further study.
研究代谢物与中年晚期认知功能之间的关联，可能会揭示与早期痴呆症相关的潜在标志物和机制。在此，我们系统地探索了在生命的第七个十年中测量的认知结果的代谢相关性，同时梳理了影响生命历程的因素。利用液相色谱 - 质谱法分析的1019种代谢物水平（年龄60 - 64岁），我们评估了英国1946年出生队列（n = 1740）中代谢物与认知结果之间的关系。我们还进行了通路和网络分析，以便更深入地了解潜在机制，并在四个模型中依次调整生命历程因素，包括性别和采血情况（模型1）、模型1 + 体重指数和脂质药物（模型2）、模型2 + 社会因素和儿童认知（模型3）以及模型3 + 生活方式影响（模型4）。在对多次检验进行校正后，155种代谢物、10条通路和5个网络模块与认知结果相关。在这155种代谢物中，有35种在其网络模块中高度连接（称为“枢纽”代谢物），是很有前景的标志物候选物。值得注意的是，我们报告了一个由酰基肉碱组成的模块与处理速度之间的关系，该关系在生命历程调整后仍然稳健，显示棕榈酰肉碱（C16）为枢纽（模型4：β = -0.10，95%置信区间 = -0.15至 -0.052，p = 5.99×10⁻⁶）。大多数关联对社会因素和儿童认知的调整敏感；在最终模型中，多次检验校正后有四种代谢物留存，p < 0.05时为80种。两个模块显示出的关联部分或大部分被生命历程因素减弱：一个富含修饰核苷和氨基酸（总体减弱 = 39.2 - 55.5%），另一个富含维生素A和C代谢物（总体减弱 = 68.6 - 92.6%）。我们的其他发现，包括一个富含鞘脂通路的模块，完全由生命历程因素解释，特别是儿童认知和教育。通过一项涵盖生命历程信息的大型出生队列研究，我们突出了与中年晚期认知功能相关的潜在代谢机制，提出了标志物候选物以及有待进一步研究的生命历程关系。
