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Brain microRNAs associated with late-life depressive symptoms are also associated with cognitive trajectory and dementia

By Aliza P. Wingo, Jingjing Yang, Wen Fan, Benjamin Logsdon, Se Min Canon, Bing Yao, Nicholas T. Seyfried, James J. Lah, Allan I. Levey, Patricia A. Boyle, Julia A. Schneider, Philip L. De Jager, David A. Bennett, Aliza P. Wingo

Posted 28 Apr 2019
bioRxiv DOI: 10.1101/620815 (published DOI: 10.1038/s41525-019-0113-8)

Objective: Late-life depression is associated with an increased risk for dementia, but our knowledge of the molecular mechanisms underlying this association is limited. Hence, the authors investigated whether microRNAs, important post-transcriptional regulators of gene expression, contribute to this association. Method: Late-life depressive symptoms were assessed annually in 300 non-demented participants of the Religious Orders Study and Rush Memory and Aging Project for a mean of seven years using the Center for Epidemiological Studies Depression scale. 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. A global microRNA association study of late-life depressive symptoms was performed using linear mixed model adjusting for sex, age, Alzheimer dementia pathological burden, proportions of brain cell types, post-mortem interval, and RNA integrity. Results: Four brain microRNAs were associated with late-life depressive symptoms at adjusted p<0.05 (miR-484, miR-26b, miR-30d, and miR-197). Lower expressions of these miRNAs were associated with greater depressive symptoms. Furthermore, lower expressions of miR-484 and miR-197 were associated with faster decline of cognitive performance over time. Additionally, lower miR-484 level was associated with higher probability of having Alzheimer dementia. Lastly, the predicted targets of miR-484 were enriched in a brain protein co-expression module involving synaptic transmission and regulation of long-term neuronal synaptic plasticity. Conclusions: This is the first study to identify brain microRNAs associated with late-life depressive symptoms assessed longitudinally. Additionally, the authors found a link between late-life depressive symptoms and dementia through miR-484 and miR-197.

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