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

• Type of Material: Article
• Authors: Aliza Wingo, Emory University; Mengli Wang, Central South University; Jiaqi Liu, Emory University; Michael S Breen, Icahn School of Medicine at Mount Sinai; Hyun-Sik Yang, Harvard Medical School; Beisha Tang, Central South University; Julie A Schneider, Rush University; Nicholas Seyfried, Emory University; James Lah, Emory University; Allan Levey, Emory University; David A Bennett, Rush University; Peng Jin, Emory University; Philip L De Jager, Broad Institute; Thomas Wingo, Emory University
• Language: English
• Date: 2022-02-01
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41398-022-01806-3
• Title of Journal or Parent Work: TRANSLATIONAL PSYCHIATRY
• Volume: 12
• Issue: 1
• Start Page: 47
• End Page: 47
• Grant/Funding Information: Support for this research was provided by the following grants from the US National Institutes of Health: R01 AG056533 (A.P.W. and T.S.W.), R01 AG036042 (D.A.B and P.L.D), R01 AG017917 (D.A.B.), RF1 AG015819 (D.A.B.), RC2 AG036547 (D.A.B.), P30 AG10161 (D.A.B.), U01 AG46152 (P.L.D.), U01 AG046161 (A.I.L.), P50 AG025688 (A.I.L.), P30 NS055077 (A.I.L.), and VA 1IK4 BX005219 (A.P.W). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: IMPAIRMENT; DEMENTIA; INSIGHTS; COMMUNITY; EXPRESSION; ALZHEIMERS-DISEASE; PATHOLOGY; TARGETS; Psychiatry; DECLINE; NETWORK; Life Sciences & Biomedicine; Science & Technology
• Research Categories: Chemistry, Biochemistry; Health Sciences, Mental Health

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.