MicroRNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer’s disease. We recently performed RNA sequencing of postmortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an antemortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to Alzheimer’s disease pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak stages III/IV compared with stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small noncoding microRNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance, and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs significantly associated (rho > 0.38, p < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation, and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak stages I-II and 47 miRNAs were associated with higher Braak stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak stages I/II vs. Braak stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau, and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and postmortem neuropathological Alzheimer’s disease diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (preclinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.