Alzheimer’s disease and related dementias (ADRD) and osteoporosis (OP) are two prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown. We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these two diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in five ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest. These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP.

中文翻译：

---

脑和骨组织转录本的网络分析揭示了阿尔茨海默病和相关痴呆症 （ADRD） 和骨质疏松症的共同分子机制


阿尔茨海默病和相关痴呆 （ADRD） 和骨质疏松症 （OP） 是两种普遍存在的衰老疾病，已证实存在流行病学关联，但导致这种关联的潜在分子机制尚不清楚。我们使用骨骼和大脑转录组的网络分析来发现这两种疾病的常见分子机制。我们的研究包括来自 ROSMAP（宗教秩序研究和 Rush 记忆与衰老项目）的 629 名参与者的尸检大脑背外侧前额叶皮层组织的 RNA 测序数据，其中 298 名亚组符合纳入五个 ADRD 类别的标准，以及来自绝经后妇女奥斯陆研究的 84 名参与者的经髂骨活检的 RNA 阵列数据。在每个组织内开发每个网络后，我们分析了具有多个骨骼和神经特征的模块 （共表达基因组） 之间的关联，检查了网络之间模块的重叠，并进行了通路富集分析以发现保守机制。我们在 ROSMAP 中发现了 3 个模块，它们与 ADRD 和骨骼相关特征有显著关联，在 Oslo 中发现了 4 个模块，它们与多种骨骼结局有显著关联。我们发现两个网络在与信号传导、组织稳态和发育相关的模块中存在显着的模块重叠，并且发现 Wingless 相关整合位点 （Wnt） 信号在感兴趣的 OP 和 ADRD 模块中高度富集。这些结果为 ADRD 和 OP 的治疗方法和生物标志物的开发提供了转化机会。