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Brain microRNAs are associated with variation in cognitive trajectory in advanced age

Wingo, Aliza P., Wang, Mengli, Liu, Jiaqi, Breen, Michael S., Yang, Hyun-Sik, Tang, Beisha, Schneider, Julie A., Seyfried, Nicholas T., Lah, James J., Levey, Allan I., Bennett, David A., Jin, Peng, De Jager, Philip L., Wingo, Thomas S.·2022·Translational Psychiatry
DOI 10.1038/s41398-022-01806-3PMC PMC8807720
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Abstract

In advancing age, some individuals maintain a stable cognitive performance over time, while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by common neurodegenerative pathologies. Hence, we aimed to identify new molecular processes underlying variation in cognitive trajectory using brain microRNA profile followed by an integrative analysis with brain transcriptome and proteome. Individual cognitive trajectories were derived from longitudinally assessed cognitive-test scores of older-adult brain donors from four longitudinal cohorts. Postmortem brain microRNA profiles, transcriptomes, and proteomes were derived from the dorsolateral prefrontal cortex. The global microRNA association study of cognitive trajectory was performed in a discovery (n = 454) and replication cohort (n = 134), followed by a meta-analysis that identified 6 microRNAs. Among these, miR-132-3p and miR-29a-3p were most significantly associated with cognitive trajectory. They explain 18.2% and 2.0% of the variance of cognitive trajectory, respectively, and act independently of the eight measured neurodegenerative pathologies. Furthermore, integrative transcriptomic and proteomic analyses revealed that miR-132-3p was significantly associated with 24 of the 47 modules of co-expressed genes of the transcriptome, miR-29a-3p with 3 modules, and identified 84 and 214 downstream targets of miR-132-3p and miR-29a-3p, respectively, in cognitive trajectory. This is the first global microRNA study of cognitive trajectory to our knowledge. We identified miR-29a-3p and miR-132-3p as novel and robust contributors to cognitive trajectory independently of the eight known cerebral pathologies. Our findings lay a foundation for future studies investigating mechanisms and developing interventions to enhance cognitive stability in advanced age.

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Metadata

Authors
Wingo, A. P., Wang, M., Liu, J., Breen, M. S., Yang, H.-S., Tang, B., Schneider, J. A., Seyfried, N. T., Lah, J. J., Levey, A. I., Bennett, D. A., Jin, P., De Jager, P. L., & Wingo, T. S.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-02-01
Volume
12
Issue
1
ISSN
2158-3188
DOI
10.1038/s41398-022-01806-3
PMC
PMC8807720
Cited by
31
References
10
Language
en
Licence
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01 AG056533)
  • U.S. Department of Veterans Affairs (VA 1IK4 BX005219)

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