microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer’s disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes.

microRNA （miRNA） 对基因表达有广泛的影响;然而，我们对它们对随着时间的推移认知能力下降率或阿尔茨海默病 （AD） 的影响了解有限。鉴于此，我们使用来自 641 名社区供体背外侧前额叶皮层的小 RNA 测序测试了 528 个 miRNA 与认知轨迹、AD 标志病理和 AD 临床诊断的关联。在调整技术和社会人口学变量后，我们发现 311 个 miRNAs 在 AD 或其内表型中差异表达。其中，137 个 miRNA 在额外调整了几种同时发生的年龄相关脑部病变后仍然差异表达，这表明一些 miRNA 通过同时发生的病理与性状相关，而另一些则通过独立于病理的机制相关。这些差异表达的 miRNA 下游靶标的通路富集分析发现，转录、突触后信号传导、细胞衰老和脂蛋白富集。在性别分层分析中，5 个 miRNA 显示一种或多种 AD 内表型的性别偏倚差异表达，突出了性别在 AD 中的作用。最后，我们使用孟德尔随机化来测试鉴定的差异表达 miRNA 是导致原因还是性状的结果。值得注意的是，15 个差异表达的 miRNAs 具有与因果作用一致的证据，为 AD 及其内表型中 miRNAs 的未来机制研究奠定了基础。