Posterior cingulate cortex microRNA alterations in cognitive resilience, mild cognitive impairment, and Alzheimer’s disease

Abstract

AbstractBackgroundMicroRNA (miRNA) dysregulation is linked to Alzheimer’s disease (AD) pathophysiology. We recently reported a role for miR‐298 and miR‐20b in AD risk and amyloid and tau metabolism. To examine the extent to which miRNAs are dysregulated during the earliest stages of AD, we quantified miRNA transcript levels in postmortem samples of posterior cingulate cortex (PCC), a default mode network (DMN) hub that underlies autobiographical memory, in normal subjects and those who died within the AD continuum.MethodPCC samples were obtained from Rush ROS/MAP participants who came to autopsy with a diagnosis of a) no cognitive impairment and low pathology (NCI‐LP, Braak stage I/II, n = 12), b) NCI with high pathology (NCI‐HP, Braak stage IV, representing cognitive resilience, n = 8), c) mild cognitive impairment (MCI, n = 10), or d) dementia due to AD (n = 9). Illumina‐based sequencing of total RNA was performed and trimmed reads with a size of 15‐31 bases were analyzed.ResultDifferential expression analysis (FDR ≤ 0.04) revealed 42 miRNAs significantly dysregulated among the NCI (independent of Braak stage), MCI, and AD groups. Two miRNAs, miR‐99a (FDR‐adjusted p = 0.01) and miR‐664b (p = 0.005), were downregulated in AD vs NCI and MCI, while miR‐30a (p = 0.006), miR‐374a (p = 0.004), and miR‐501 (p = 0.005) were significantly upregulated in MCI vs. NCI and AD. Three miRNAs were significantly downregulated in NCI‐HP vs. NCI‐LP: miR‐103a (p = 0.04), miR‐211 (p = 0.03), and miR‐4443 (p = 0.03). These miRNAs may operate in resilience‐related pathways. Correlation analysis revealed that decreasing PCC levels of miR‐664b levels were associated with poorer performance on antemortem tests of episodic memory (r = 0.41, p = 0.009), semantic memory (r = 0.44, p = 0.004), and visuospatial ability (r = 0.45, p = 0.004).ConclusionTaken together, these data may identify potential pathogenic or protective miRNA‐related mechanisms contributing to PCC and DMN function during the progression of AD, which may inform biomarker and intervention strategies. Ongoing analysis will identify functional pathway enrichment and miRNA targets.