Uncovering Spatiotemporal and Functional Dynamics of Long Non-coding RNAs During Alzheimer’s Progression in the Human Brain at Single-Cell Resolution

Abstract

Increasing prevalence of Alzheimer’s disease, driven by population aging, highlights the need to investigate its underlying molecular mechanisms. Within this context, long non-coding RNAs (lncRNAs) have emerged as a key regulatory layer. To advance the understanding of lncRNA dysregulation and function during Alzheimer’s disease progression, we reanalyzed publicly available single-nucleus RNA sequencing (snRNA-seq) datasets. The selected transcriptomic datasets were integrated and subjected to differential expression and genomic co-localization correlation analyses to infer putative cis -regulatory mechanisms. Our results reveal conserved cell-type composition and a shared transcriptional trajectory across brain regions during Alzheimer’s disease progression. In contrast, lncRNAs displayed marked cell-type and context specificity and formed coordinated expression patterns with neighboring genes within defined chromatin contexts. These associations suggest potential cis -regulatory roles and implicate lncRNAs in processes such as synaptic plasticity and maladaptive oligodendrocyte differentiation linked to myelin dysfunction. While these findings are primarily hypothesis-generating, they provide a cross-regional framework and a prioritized set of candidate lncRNAs for future functional investigation in Alzheimer’s disease.

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