miR-423-5p and miR-92a-3p in Alzheimer's disease: relationship with pathology and cognition

Sang-Won Han^1,2Young Ho Park^3,4*Jung-Min Pyun³Paula J. Bice⁵SangYun Kim^2,3Andrew J. Saykin⁵Kwangsik Nho^5*

• ¹Soonchunhyang University Hospital, Yongsan-gu, Republic of Korea
• ²Soonchunhyang University College of Medicine, Cheonan-si, Republic of Korea
• ³Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea
• ⁴Seoul National University College of Medicine, Jongno-gu, Republic of Korea
• ⁵Indiana University School of Medicine, Indianapolis, United States

Background: MicroRNAs (miRNAs), small and highly conserved non-coding RNA molecules, have emerged as promising molecular biomarkers due to their regulatory roles in gene expression and stability in blood. Methods: We used measurements of 64 plasma miRNAs from 145 participants in the Alzheimer's Disease Neuroimaging Initiative cohort, including 74 probable AD patients and 71 cognitively normal (CN) older adults. We performed principal component analysis (PCA) with factor rotation for dimension reduction to identify AD-associated principal components (PCs) and their key miRNAs with factor loadings higher than 0.8. We investigated their association with amyloid/tau/neurodegeneration (A/T/N) biomarkers and cognition. After identifying the candidate target genes of key miRNAs, we performed pathway enrichment analysis. We conducted mediation analyses to assess the effect of the associations between miRNAs and A/T/N biomarkers on AD diagnosis and cognition. Finally, we used a machine learning approach to evaluate the performance of key miRNAs for AD classification. Results: PCA identified one PC as significantly associated with AD. The PC was also significantly associated with CSF p-tau levels, hippocampal volume, and cognition. Two key miRNAs (miR-423-5p and miR-92a-3p) in the PC were associated with AD. Lower levels of miR-423-5p and miR-92a-3p were associated with reduced hippocampal volume and worse cognition, and lower levels of miR-423-5p were associated with higher brain amyloid deposition. Pathway enrichment analysis identified several significant biological processes, including memory, protein phosphorylation, and the phosphatidylinositol-3-phosphate biosynthetic process. Mediation analysis revealed that miR-423-5p, but not miR-92a-3p, had indirect effects on AD diagnosis and memory performance through brain amyloid deposition and brain atrophy. Machine learning analysis demonstrated that incorporating two key miRNAs improved the performance of demographic information for AD classification. Conclusions: Plasma miR-423-5p and miR-92a-3p are implicated in AD pathology and cognitive decline, providing insights into their roles in disease mechanisms. This study suggests the potential of these miRNAs as blood-based molecular biomarkers for AD.