Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Long noncoding RNAs (lncRNAs) are implicated in Alzheimer's disease (AD) pathogenesis.
• Their specific roles in cognitive decline are not fully understood.
• This study investigates lncRNAs in AD using multi-omics and machine learning.

Purpose of the Study:

• To identify lncRNAs associated with cognitive decline in Alzheimer's disease.
• To elucidate the molecular mechanisms underlying lncRNA involvement in AD.
• To integrate multi-omics data for a comprehensive understanding of AD pathology.

Main Methods:

• Machine learning analysis of multi-modal omics data from cortical regions (parietal cortex, dorsolateral prefrontal cortex, parahippocampal gyrus).
• Identification of protein-coding genes and their interactions with dysregulated lncRNAs via gene regulatory networks, co-expression, and protein-protein interaction analyses.
• Gene set enrichment and pathway analyses to explore lncRNA regulatory roles.

Main Results:

• Multi-omics integration revealed an AD molecular profile associated with worse cognition, faster progression, and neurodegeneration.
• 177 dysregulated lncRNAs, termed WCFALs (Worse Cognitive Function Associated lncRNAs), were identified across cohorts.
• WCFAL1, the most upregulated lncRNA, strongly correlated with worse cognitive profiles and FOXN3, a microglial regulator, and interacted with SIN3A, linked to amyloid-beta.

Conclusions:

• lncRNAs are linked to worse cognitive function in Alzheimer's disease.
• WCFAL1 is a key lncRNA potentially regulating microglial activity via FOXN3 or the FOXN3-SIN3A pathway.
• Further experimental validation of WCFAL1's function is warranted.