Genome‐wide profiling of circulatory microRNAs associated with cognition and dementia

Abstract

Introduction: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Their role in the pathophysiology of dementia and potential as biomarkers remains undetermined. Methods: We conducted a single-(one-by-one) and multi-marker (joint) analysis to identify well-expressed circulating miRNAs in plasma (total = 591) associated with general cognition and incident dementia, for 1615 participants of the population-based Rotterdam Study.Results: During single-marker analysis, 47 miRNAs were nominally (P ≤ .05) associated with cognition and 18 miRNAs were nominally associated with incident dementia, after adjustment for potential confounders. Three miRNAs were common between cognition and dementia (miR-4539, miR-372-3p, and miR-566), with multi-marker analysis revealing another common miRNA (miR-7106-5p). In silico analysis of these four common miRNAs led to several putative target genes expressed in the brain, highlighting the mitogen-activated protein kinase signaling pathway. Discussion: We provide population-based evidence on the relationship between circulatory miRNAs with cognition and dementia, including four common miRNAs that may elucidate downstream mechanisms.

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.…”

“…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.…”

“…However, most of these studies had relatively small samples, potentially limiting their capability to detect microRNAs with weaker effect sizes. Specifically, the largest study included 1615 participants [12], while the rest had sample sizes ranging from 132 [16] to 830 [15] participants. Moreover, the only study that examined more than one cognitive domain evaluated only a small number (n=38) of microRNAs previously linked to AD [15].…”

“…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].…”

MicroRNAs as Potential Biomarkers of Mental Disorders: Diagnostic and Prognostic Implications

“…Имеющиеся научные данные свидетельствуют о возможности использования miR-92a-3p и miR-532-5p не только в качестве биомаркеров когнитивных функций, но и в контексте изучения молекулярных механизмов заболеваний, сопровождающихся когнитивным снижением [57]. Три микроР-НК оказались общими для когнитивного расстройства и деменции (miR-4539, miR-372-3p и miR-566), а мультимаркерный анализ выявил еще одну общую микроРНК (miR-7106-5p) [58]. Анализ этих четырех общих микроР-НК позволил обнаружить несколько предполагаемых генов-мишеней, экспрессирующихся в головном мозге, и выделить сигнальный путь соответствующей митоген-активированной протеинкиназы.…”