Chen C, Zhang Z, Liu Y, Hong W, Karahan H, Wang J, Li W, Diao L, Yu M, Saykin AJ, Nho K, Kim J, Han L. Comprehensive characterization of the transcriptional landscape in Alzheimer's disease (AD) brains. Sci Adv. 2025 Jan 3;11(1):eadn1927. Epub 2025 Jan 3 PubMed.
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German Center for Neurodegenerative Disease (DZNE)
The Expanding Role of RNA Therapeutics in Alzheimer's Disease Research
Translational research over the past decades has primarily focused on protein-coding genes, which make up only 1.5 percent of the human genome. However, many of these genes are considered undruggable, a limitation underscored by the fact that, to date, only a little over 800 protein drug targets have received FDA approval across all human diseases (Human Protein Atlas). In contrast, the remaining 98.5 percent of the transcribed genome, long dismissed as “junk DNA,” consists of noncoding RNAs (ncRNAs). These include small ncRNAs, such as microRNAs, which have emerged as promising biomarkers for Alzheimer’s disease and may help to define specific disease stages (Krüger et al., 2024; Liu et al., 2024). Another key category is long noncoding RNAs (lncRNAs), which are increasingly recognized for their roles in gene regulation and neurodegeneration (Mattick et al., 2023).
The past decade has witnessed a paradigm shift in our understanding of ncRNA function, coinciding with rapid advancements in RNA-based therapeutics, which are now transitioning from bench to clinical application at an unprecedented pace (Winkle et al., 2021). However, despite this progress, RNA therapeutics in brain diseases remain relatively underexplored. In this context, this study by Chen et al. represents a major breakthrough, offering a comprehensive catalog of ncRNAs and RNA editing in AD brains. By systematically analyzing 1,460 postmortem brain samples, the authors identified thousands of deregulated noncoding RNAs and post-transcriptional RNA editing events across multiple brain regions. Their publicly available ADatlas provides an invaluable resource for investigating RNA-based mechanisms in neurodegeneration and offers novel insights into enhancer RNAs (eRNAs), alternative polyadenylation (APA) events, RNA editing, and long noncoding RNAs (lncRNAs) in AD.
LncRNAs, in particular, are of growing interest due to their essential roles in regulating gene expression, chromatin structure, mRNA translation, and stability. While previous studies have implicated lncRNAs in tau pathology and amyloid pathology, only recently have researchers begun to systematically explore their potential as therapeutic targets and biomarkers in AD (Schröder et al., 2024; Schröder et al., 2025). This emerging field holds immense potential for expanding the space for drug discovery in neurodegenerative diseases, including AD. One major advantage of lncRNAs as drug targets is their cell-type and tissue-specific expression patterns, with up to 40 percent of human lncRNAs reported to be brain specific (Derrien et al., 2012). These properties make them attractive candidates for precision medicine approaches, further reinforcing the significance of the ADatlas dataset.
In the broader field of RNA therapeutics, it is essential to distinguish between two key approaches: ncRNAs acting as drugs, and ncRNAs serving as drug targets. In the first approach, siRNAs or miRNAs are designed to reduce the expression of disease-associated proteins. A striking example is ALN-APP, an investigational RNA interference (RNAi) therapeutic developed by Alnylam Pharmaceuticals, which targets amyloid precursor protein (APP) for the treatment of AD and cerebral amyloid angiopathy. Meanwhile, the second approach focuses on targeting ncRNAs themselves, using antisense oligonucleotides (ASOs) or other RNA-based modalities to modulate their function. Although this approach is still in preclinical stages for AD, promising data exist for other postmitotic and excitable tissues, such as the heart. Recent clinical findings suggest that targeting a specific microRNA could be therapeutic for heart failure (Bauersachs et al., 2024), a breakthrough that prompted Novo Nordisk to acquire the correspoding start-up company.
These developments reflect a broader trend in pharmaceutical research, where RNA-based therapeutics are gaining traction as powerful tools for modulating disease processes. The comprehensive dataset provided by Chen et al. could serve as a blueprint for identifying novel RNA-based drug candidates, potentially enabling researchers to target ncRNAs that play a key role in AD pathogenesis.
However, a significant challenge remains: distinguishing causative from correlative changes in the noncoding transcriptome. While ADatlas offers a high-resolution snapshot of RNA alterations, further functional studies are necessary to determine the exact role of specific ncRNAs in disease progression.
Overall, the study by Chen et al. represents a major milestone in AD research, reinforcing the need to further explore ncRNAs and RNA-based interventions in the ongoing search for effective AD treatments. As the field of RNA therapeutics continues to evolve, these discoveries may pave the way for novel precision medicine strategies targeting neurodegenerative diseases.
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