Posterior cingulate cortex microRNA dysregulation differentiates cognitive resilience, mild cognitive impairment, and Alzheimer's disease

Abstract

Introduction: MicroRNA (miRNA) activity is increasingly appreciated as a key regulator of pathophysiologic pathways in Alzheimer's disease (AD). However, the role of miRNAs during the progression of AD, including resilience and prodromal syndromes such as mild cognitive impairment (MCI), remains underexplored.

Methods: We performed miRNA-sequencing on samples of posterior cingulate cortex (PCC) obtained post mortem from Rush Religious Orders Study participants diagnosed ante mortem with no cognitive impairment (NCI), MCI, or AD. NCI subjects were subdivided as low pathology (Braak stage I/II) or high pathology (Braak stage III/IV), suggestive of resilience. Bioinformatics approaches included differential expression, messenger RNA (mRNA) target prediction, interactome modeling, functional enrichment, and AD risk modeling.

Results: We identified specific miRNA groups, mRNA targets, and signaling pathways distinguishing AD, MCI, resilience, ante mortem neuropsychological test performance, post mortem neuropathological burden, and AD risk.

Discussion: These findings highlight the potential of harnessing miRNA activity to manipulate disease-modifying pathways in AD, with implications for precision medicine.

Highlights: MicroRNA (MiRNA) dysregulation is a well-established feature of Alzheimer's disease (AD). Novel miRNAs also distinguish subjects with mild cognitive impairment and putative resilience. MiRNAs correlate with cognitive performance and neuropathological burden. Select miRNAs are associated with AD risk with age as a significant covariate. MiRNA pathways include insulin, prolactin, kinases, and neurite plasticity.

Keywords: dementia; microRNA; mild cognitive impairment; non‐coding RNA; resilience.

FIGURE 1

Putative protein–protein interactions and pathways of genes targeted by differentially expressed miRNAs PCC of AD subjects. A, STRING interactome diagram shows putative functional relationships among mRNAs targeted by AD‐specific miRNAs. Pathview diagrams show functionally enriched (B) insulin and (C) mTOR signaling pathways. Genes/proteins in red are functional interaction nodes for mRNA targets of AD‐related miRNAs in PCC. AD, Alzheimer's disease; miRNAs, microRNAs; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; PCC, posterior cingulate cortex; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins

FIGURE 2

Putative protein–protein interactions and pathways of genes targeted by miRNAs upregulated in PCC of MCI compared to NCI and AD subjects. A, STRING interactome diagram show putative functional relationships among mRNAs targeted by MCI‐specific miRNAs. Pathview diagrams show functionally enriched (B) prolactin and (C) MAPK signaling pathways. Genes/proteins in red are functional interaction nodes for mRNA targets of miRNAs upregulated in PCC of MCI subjects. *, MAPK pathway interaction nodes for AD‐related miRNAs; #, MAPK pathway interaction nodes for resilience‐related miRNAs. AD, Alzheimer's disease; MAPK, mitogen‐activated protein kinase; MCI, mild cognitive impairment; miRNAs, microRNAs; mRNA, messenger RNA; NCI, no cognitive impairment; PCC, posterior cingulate cortex; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.

FIGURE 3

Putative protein–protein interactions and pathways of genes targeted by resilience‐related miRNAs differentially expressed in PCC of NCI‐HP compared to NCI‐LP subjects. A, STRING interactome diagram show putative functional relationships among mRNAs targeted by resilience‐associated miRNAs. Pathview diagrams show functionally enriched (B) Dorso‐ventral axis formation and (C) focal adhesion pathways. Genes/proteins in red are functional interaction nodes for mRNA targets of miRNAs differentially expressed in NCI‐HP versus NCI‐LP subjects. NCI‐HP, no cognitive impairment patients with high AD pathology; NCI‐LP, no cognitive impairment patients with low AD pathology; miRNAs, microRNAs; mRNA, messenger RNA; PCC, posterior cingulate cortex; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.

FIGURE 4

Relationship between miR‐32 (A–C) and miR‐3560 (D–F) miRNA levels and percent probabilities of NCI‐LP (), NCI‐HP (), MCI (), and AD () at ages 75–85 (A,D), 85–90 (B,E), and 90–96 (C,F). AD, Alzheimer's disease; MCI, mild cognitive impairment; miRNAs, microRNAs; NCI‐HP, no cognitive impairment patients with high AD pathology; NCI‐LP, no cognitive impairment patients with low AD pathology.