BACKGROUND Substantial evidence supports the relationship between peripheral insulin resistance (IR) and the development of Alzheimer’s disease (AD)-dementia. However, the mechanisms explaining these associations are only partly understood. We aimed to identify a metabolic signature of IR associated with the progression from mild cognitive impairment (MCI) to AD-dementia. METHODS This is a case-control study on 400 MCI subjects, free of type 2 diabetes, within the ACE cohort, including individuals ATN+ and ATN-. After a median of 2.1 years follow-up, 142 subjects converted to AD-dementia. IR was assessed using the HOMA-IR. A targeted multi-platform approach profiled over 600 plasma metabolites. Elastic net penalized linear regression with 10-fold cross-validation was employed to select those metabolites associated with HOMA-IR. The prediction ability of the signature was assessed using support vector machine and performance metrics. The metabolic signature was associated with AD-dementia risk using a multivariable Cox regression model. Using counterfactual-based mediation analysis we investigated the mediation role of the metabolic signature between HOMA-IR and AD-dementia. The metabolic pathways in which the metabolites were involved were identified using MetaboAnalyst. RESULTS The metabolic signature comprised 18 metabolites correlated with HOMA-IR. After adjustments by confounders, the signature was associated with increased AD-dementia risk (HR 1.234; 95%CI 1.019-1.494; p<0.05). The metabolic signature mediated 35% of the total effect of HOMA-IR on AD-dementia risk. Significant metabolic pathways were related to glycerophospholipid and tyrosine metabolism. CONCLUSIONS We have identified a blood-based metabolic signature that reflects IR and may enhance our understanding of the biological mechanisms through which IR affects AD-dementia.

中文翻译：

---

胰岛素抵抗的代谢特征和阿尔茨海默病的风险


背景 大量证据支持外周胰岛素抵抗 （IR） 与阿尔茨海默病 （AD） 痴呆发展之间的关系。然而，解释这些关联的机制仅部分了解。我们旨在确定与从轻度认知障碍 （MCI） 进展为 AD 痴呆相关的 IR 代谢特征。方法 这是一项对 ACE 队列中 400 名无 2 型糖尿病的 MCI 受试者的病例对照研究，包括个体 ATN+ 和 ATN-。经过中位 2.1 年的随访，142 名受试者转化为 AD 痴呆。使用 HOMA-IR 评估 IR。靶向多平台方法分析了 600 多种血浆代谢物。采用具有 10 倍交叉验证的弹性网惩罚线性回归来选择与 HOMA-IR 相关的代谢物。使用支持向量机和性能指标评估签名的预测能力。使用多变量 Cox 回归模型，代谢特征与 AD 痴呆风险相关。使用基于反事实的中介分析，我们研究了 HOMA-IR 和 AD 痴呆之间代谢特征的中介作用。使用 MetaboAnalyst 确定代谢物参与的代谢途径。结果 代谢特征包括 18 种与 HOMA-IR 相关的代谢物。经过混杂因素调整后，特征与 AD 痴呆风险增加相关 （HR 1.234;95%CI 1.019-1.494;p<0.05）。代谢特征介导了 HOMA-IR 对 AD 痴呆风险总影响的 35%。重要的代谢途径与甘油磷脂和酪氨酸代谢有关。 结论 我们已经确定了一种反映 IR 的基于血液的代谢特征，并可能增强我们对 IR 影响 AD 痴呆的生物学机制的理解。