Turnbull Adam, Kim Yejin, Zhang Kai, Jiang Xiaoqian, He Zihuai, Henderson Victor W, Lin F Vankee
CogT Lab, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Geroscience. 2025 Apr;47(2):1501-1515. doi: 10.1007/s11357-024-01291-0. Epub 2024 Jul 31.
The structural connectivity (SC) of the medial temporal lobe and its associated cortical anterior temporal and posterior medial networks (MTL-AT-PM) is linked to pathologies and memory decline in Alzheimer's disease (AD). However, neuroimaging analyses cannot tell us how SC changes occur in AD at the molecular level and do not provide a means of intervening to slow/prevent pathology-related changes in MTL-AT-PM SC. The current study aimed to understand how and where AD-related changes occur within MTL-AT-PM using proteomics. We used a 4-step approach in 101 older adults from a local sample, aiming to understand how proteins and SC in combination at the multivariate level predict AD pathology, and to identify specific proteins related to SC and AD pathology. Separately, we validated the discovered proteins in relation to SC and AD pathology using ADNI sample. We identified 12 latent factors linking proteins and SC; five showed significant relationships with AD pathology and/or episodic memory. Insulin-like growth factor binding proteins and tumor necrosis factor receptors, and hippocampal/parahippocampal edges contributed most to AD-related latent factors. Fast causal inference found protein-protein, protein-SC, and protein-pathology pathways, with seven proteins showing directional links to SC and AD-related neurodegeneration. We validated these results by identifying significant relationships between six available proteins with SC and amyloid-beta and phosphorylated tau in ADNI. We identified multivariate relationships between proteins and MTL-AT-PM networks that add to our understanding of AD pathology and suggest specific non-pathological proteins that warrant further study in relation to brain networks and AD pathology as possible therapeutic targets.
内侧颞叶及其相关的皮质前颞叶和后内侧网络（MTL-AT-PM）的结构连通性（SC）与阿尔茨海默病（AD）的病理变化和记忆衰退有关。然而，神经影像学分析无法告诉我们AD中SC变化在分子水平上是如何发生的，也没有提供一种干预手段来减缓/预防MTL-AT-PM SC中与病理相关的变化。当前的研究旨在使用蛋白质组学来了解AD相关变化在MTL-AT-PM内如何以及在何处发生。我们对来自当地样本的101名老年人采用了四步方法，旨在了解蛋白质和SC在多变量水平上如何联合预测AD病理，并识别与SC和AD病理相关的特定蛋白质。另外，我们使用ADNI样本验证了发现的与SC和AD病理相关的蛋白质。我们确定了12个连接蛋白质和SC的潜在因素；其中5个与AD病理和/或情景记忆显示出显著关系。胰岛素样生长因子结合蛋白和肿瘤坏死因子受体，以及海马/海马旁边缘对AD相关潜在因素的贡献最大。快速因果推断发现了蛋白质-蛋白质、蛋白质-SC和蛋白质-病理途径，有7种蛋白质显示出与SC和AD相关神经退行性变的定向联系。我们通过确定ADNI中6种可用蛋白质与SC、淀粉样β蛋白和磷酸化tau蛋白之间的显著关系来验证这些结果。我们确定了蛋白质与MTL-AT-PM网络之间的多变量关系，这加深了我们对AD病理的理解，并提出了特定的非病理性蛋白质，这些蛋白质作为可能的治疗靶点，在与脑网络和AD病理相关方面值得进一步研究。
