阿尔茨海默病（AD）神经元功能障碍的分子机制仍不清楚。在这里，我们确定了与活人大脑中淀粉样蛋白 (Aβ) 和 tau 沉积物引起的全脑失调相关的基因、分子途径和细胞成分。我们获得了衰老和痴呆转化生物标志物队列中 47 名认知未受损和 16 名 AD 参与者的体内静息态功能 MRI (rs-fMRI)、Aβ- 和 tau-PET。通过将病理介导的计算信号与参与者的真实 rs-fMRI 相拟合，用个性化动力学模型量化 Aβ 和 tau 的不利神经元活动影响。然后，我们检测到 Aβ-tau 影响的空间分布与神经典型转录组中的基因表达之间存在强大的全脑关联（艾伦人脑图谱）。在获得的体内神经元功能障碍的独特特征中，几个基因在小胶质细胞激活以及与 Aβ 和 tau 相互作用中发挥着重要作用。此外，细胞脆弱性估计揭示了小胶质细胞表达模式与 Aβ 和 tau 对神经元活动的协同影响密切相关 (q < 0.001)。这些结果进一步支持了免疫系统和神经炎症通路在 AD 发病机制中的核心作用。 AD 病理引起的神经元失调也与神经典型突触和发育过程有关。此外，我们从庞大的 LINCS 库中确定了候选药物，以阻止或减少观察到的 Aβ-tau 对神经元活动的影响。排名靠前的药物干预措施针对炎症、癌症和心血管途径，包括正在进行 AD 临床评估的特定药物。我们的研究结果基于对人类分子病理功能相互作用的检查，可能会加速将有效疗法引入临床实践的进程。版权所有 © 2024 Sanchez-Rodriguez, Khan, Adewale, Bezgin, Therriault, Fernandez-Arias, Servaes,拉赫穆尼、蒂索、史蒂文森、江、柴、卡博内尔、罗莎-内托和伊图里亚-麦地那。

The molecular mechanisms underlying neuronal dysfunction in Alzheimer's disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant's real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau's synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aβ-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.Copyright © 2024 Sanchez-Rodriguez, Khan, Adewale, Bezgin, Therriault, Fernandez-Arias, Servaes, Rahmouni, Tissot, Stevenson, Jiang, Chai, Carbonell, Rosa-Neto and Iturria-Medina.