Late-life depression is associated with an increased risk for dementia but we have limited knowledge of the molecular mechanisms underlying this association. Here we investigated whether brain microRNAs, important posttranscriptional regulators of gene expression, contribute to this association. Late-life depressive symptoms were assessed annually in 300 participants of the Religious Orders Study and Rush Memory and Aging Project for a mean of 7 years. Participants underwent annual cognitive testing, clinical assessment of cognitive status, and uniform neuropathologic examination after death. microRNAs were profiled from the prefrontal cortex using NanoString platform in the discovery cohort and small RNA sequencing in the replication cohort. A global microRNA association study of late-life depressive symptoms was performed using linear mixed model adjusting for the potential confounding factors. Four brain microRNAs were associated with late-life depressive symptoms at adjusted p < 0.05: miR-484, miR-26b-5p, miR-30d-5p, and miR-197-3p. Lower expression levels of these miRNAs were associated having greater depressive symptoms. Furthermore, lower levels of miR-484 and miR-197-3p were associated with faster decline of cognition over time. Moreover, lower miR-484 level was associated with higher probability of having Alzheimer's dementia. Importantly, the associations between miR-484 and depressive symptoms and Alzheimer's dementia, respectively, were replicated in an independent cohort. Lastly, the predicted targets of miR-484 were enriched in a brain protein co-expression module involving synaptic transmission and regulation of synaptic plasticity. This study identified four brain microRNAs associated with late-life depressive symptoms assessed longitudinally. In addition, we found a molecular connection between late-life depression and dementia through miR-484.

中文翻译：

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与晚期抑郁症状相关的大脑microRNA也与认知轨迹和痴呆症相关。

晚期抑郁症与痴呆症的风险增加有关，但我们对这种关联背后的分子机制的了解有限。在这里，我们调查了大脑microRNAs，基因表达的重要转录后调节因子，是否有助于这种关联。每年对300名“宗教秩序研究”和“仓促记忆和衰老项目”的参与者进行评估，以评估他们的晚期抑郁症状，平均持续7年。参加者每年接受一次认知测试，对认知状态进行临床评估，并在死亡后进行统一的神经病理学检查。在发现队列中使用NanoString平台从前额叶皮层分析microRNA，在复制队列中使用小RNA测序。一项针对晚期抑郁症状的全球microRNA关联研究使用线性混合模型进行了调整，以调整潜在的混杂因素。在调整的p <0.05时，四种大脑microRNA与晚期抑郁症状相关：miR-484，miR-26b-5p，miR-30d-5p和miR-197-3p。这些miRNA的较低表达水平与抑郁症状相关。此外，较低水平的miR-484和miR-197-3p与随着时间的推移认知能力下降较快有关。此外，较低的miR-484水平与罹患老年痴呆症的可能性较高相关。重要的是，miR-484与抑郁症状和阿尔茨海默氏痴呆症之间的关联分别在独立的队列中复制。最后，miR-484的预测靶点富含脑蛋白共表达模块，涉及突触传递和突触可塑性调节。这项研究确定了与纵向评估的晚期抑郁症状相关的四种大脑microRNA。此外，我们通过miR-484发现了晚期抑郁症和痴呆症之间的分子联系。