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

Authors

Scott E. Counts, Department of Translational Neuroscience, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA.
John S. Beck, Department of Translational Neuroscience, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA.
Bryan Maloney, Departments of Psychiatry and Medical and Molecular Genetics, Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Michael Malek-Ahmadi, Banner Alzheimer's Institute, Phoenix, Arizona, USA.
Stephen D. Ginsberg, Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, USA.
Elliott J. Mufson, Departments of Translational Neuroscience and Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Debomoy K. Lahiri, Departments of Psychiatry and Medical and Molecular Genetics, Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Document Type

Article

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

Medical Subject Headings

Humans; Cognitive Dysfunction (genetics, pathology, metabolism); Alzheimer Disease (genetics, pathology, metabolism); Gyrus Cinguli (metabolism, pathology); MicroRNAs (metabolism, genetics); Male; Female; Aged; Aged, 80 and over; Neuropsychological Tests

Publication Date

2-1-2025

Publication Title

Alzheimer's & dementia : the journal of the Alzheimer's Association

E-ISSN

1552-5279

Volume

21

Issue

2

First Page

e70019

PubMed ID

40008917

Digital Object Identifier (DOI)

10.1002/alz.70019

Recommended Citation

Counts, Scott E.; Beck, John S.; Maloney, Bryan; Malek-Ahmadi, Michael; Ginsberg, Stephen D.; Mufson, Elliott J.; and Lahiri, Debomoy K., "Posterior cingulate cortex microRNA dysregulation differentiates cognitive resilience, mild cognitive impairment, and Alzheimer's disease" (2025). Translational Neuroscience. 2476.
https://scholar.barrowneuro.org/neurobiology/2476