Research Paper Volume 14, Issue 17 pp 6859—6886

Extracellular microRNA and cognitive function in a prospective cohort of older men: The Veterans Affairs Normative Aging Study

Nicole Comfort1, , Haotian Wu1, , Peter De Hoff2, , Aishwarya Vuppala2, , Pantel S. Vokonas3,4, , Avron Spiro5,6,7, , Marc Weisskopf8, , Brent A. Coull9, , Louise C. Laurent2, , Andrea A. Baccarelli1, , Joel Schwartz8, ,

  • 1 Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY 10032, USA
  • 2 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego, La Jolla, CA 92093, USA
  • 3 VA Normative Aging Study, VA Boston Healthcare System, Boston, MA 02130, USA
  • 4 Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
  • 5 Massachusetts Veterans Epidemiology and Research Information Center, VA Boston Healthcare System, Boston, MA 02130, USA
  • 6 Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA
  • 7 Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA
  • 8 Department of Environmental Health, Harvard TH Chan School of Public Health, Boston, MA 02115, USA
  • 9 Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA 02115, USA

Received: March 29, 2022       Accepted: August 17, 2022       Published: September 6, 2022
How to Cite

Copyright: © 2022 Comfort et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Aging-related cognitive decline is an early symptom of Alzheimer’s disease and other dementias, and on its own can have substantial consequences on an individual’s ability to perform important everyday functions. Despite increasing interest in the potential roles of extracellular microRNAs (miRNAs) in central nervous system (CNS) pathologies, there has been little research on extracellular miRNAs in early stages of cognitive decline. We leverage the longitudinal Normative Aging Study (NAS) cohort to investigate associations between plasma miRNAs and cognitive function among cognitively normal men.

Methods: This study includes data from up to 530 NAS participants (median age: 71.0 years) collected from 1996 to 2013, with a total of 1,331 person-visits (equal to 2,471 years of follow up). Global cognitive function was assessed using the Mini-Mental State Examination (MMSE). Plasma miRNAs were profiled using small RNA sequencing. Associations of expression of 381 miRNAs with current cognitive function and rate of change in cognitive function were assessed using linear regression (N = 457) and linear mixed models (N = 530), respectively.

Results: In adjusted models, levels of 2 plasma miRNAs were associated with higher MMSE scores (p < 0.05). Expression of 33 plasma miRNAs was associated with rate of change in MMSE scores over time (p < 0.05). Enriched KEGG pathways for miRNAs associated with concurrent MMSE and MMSE trajectory included Hippo signaling and extracellular matrix-receptor interactions. Gene targets of miRNAs associated with MMSE trajectory were additionally associated with prion diseases and fatty acid biosynthesis.

Conclusions: Circulating miRNAs were associated with both cross-sectional cognitive function and rate of change in cognitive function among cognitively normal men. Further research is needed to elucidate the potential functions of these miRNAs in the CNS and investigate relationships with other neurological outcomes.


AD: Alzheimer’s disease; APOE: Apolipoprotein-E; Bp: Base pair; CANTAB: Cambridge Neuropsychological Test Automated Battery; CNS: Central nervous system; CoA: Coenzyme A; CSF: Cerebrospinal fluid; ECM: Extracellular matrix; exRNA: Extracellular RNA; EV: Extracellular vesicle; FDR: False Discovery Rate; KEGG: Kyoto Encyclopedia of Genes and Genomes; MET-hrs: Metabolic equivalent of task hours; miRNA: microRNA; mRNA: messenger RNA; MMSE: Mini-Mental State Examination; NAS: Normative Aging Study; qRT-PCR: quantitative real-time PCR; RNA-seq: next-generation RNA sequencing; SD: Standard deviation; TGF-β: Transforming growth factor beta; TMM: Trimmed mean of M; U.S.: United States; VA: Department of Veterans’ Affairs.