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

Abstract

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. www.aging-us.com 6860 AGING* For N = 457, the first visit occurred at the baseline visit, i.e., the same visit when blood was drawn for the plasma miRNA measure. The remaining 73 participants had their first MMSE measure occur after the baseline plasma assessment.

Circulating microRNAs are related to cognitive domains in the general population

“…Among the 46 microRNAs associated with cognition in previous population-based studies, miR-340-5p, miR-125b-5p, mir-4732-3p and miR-92a-3p were associated with at least one cognitive score in the same direction in our per microRNA analysis. Of note, miR-4732-3p had been found in two of the previous studies [12,13] and, among these 46 microRNAs, it had the strongest association with cognition in our data. Conversely, seven microRNAs were significantly associated with cognitive scores in the opposite direction in our data, compared to previous studies.…”

“…Seven microRNAs, including the abovementioned miR-215-5p, were inconsistently associated with cognition in our study and in previous studies by Comfort et al and Yaqub et al. [12,13] (Section 3.2.1). As these previous studies included older participants compared to ours, the inconsistent associations of microRNAs with cognition might have been driven by age-dependent effects.…”

“…Conversely, seven microRNAs were significantly associated with cognitive scores in the opposite direction in our data, compared to previous studies. Six of these microRNAs, miR-30e-3p, miR-342-5p, miR-574-5p, miR-320c, miR-215-5p, miR-320b, miR-122-5p, came from the same study by Comfort et al [13], which had included older (median age: 71 years) and only male participants. The seventh microRNA, miR-122-5p, had been identified in a study by Yaqub et al [12], which also included older participants (median age: 70.3 years) compared to our study ( Figures 1A & 1B ).…”

“…The first part of our per microRNA analysis consisted of a replication analysis for a priori selected microRNAs. This included 46 microRNAs associated with cognition in previous similar studies [12][13][14][15][16], and 10 microRNAs consistently found to be differentially expressed in the blood of AD and Mild Cognitive Impairment (MCI) patients in a recent meta-analysis [17]. An overview of these studies can be found in Supplementary Table S1.…”

“…To assess whether circulating microRNAs can be employed for early detection or prevention of cognitive dysfunction, their association with cognition must be investigated in non-demented individuals, and their functions must be better understood. In the past, a few population-based studies identified microRNA signatures associated with general cognitive function and decline [12,13], verbal memory changes longitudinally [14], or multiple cognitive domains cross-sectionally [15]. A recent study identified a three-microRNA signature related to cognitive function and decline, by combining population-level and animal model data [16].…”