Epigenetic Pathways and Human iPSC-Derived Models: Towards Next-Generation Alzheimer’s Disease Therapies

Alzheimer’s disease (AD) remains one of the most pressing neurodegenerative disorders worldwide, characterized by progressive memory loss, synaptic dysfunction, and neurodegeneration. Despite extensive studies in traditional animal models, translational success has been limited, underscoring the urgent need for human-relevant systems to uncover novel mechanisms and therapeutic targets. Recent advances in epigenetics have revealed that histone modifications, DNA methylation, and non-coding RNAs regulate key genes implicated in synaptic plasticity, neuroinflammation, and tau pathology. At the same time, induced pluripotent stem cell (iPSC)-derived brain organoids and assembloids have emerged as powerful tools to model human-specific neuronal and glial interactions. The convergence of these fields provides a unique opportunity to dissect disease mechanisms and identify innovative therapeutic strategies for AD.

This Research Topic aims to bridge epigenetic regulation and advanced human stem cell–derived models to accelerate the discovery of mechanisms and therapies for Alzheimer’s disease. The objective is twofold: first, to understand how epigenetic dysregulation contributes to pathological hallmarks of AD, including tau hyperphosphorylation, amyloid processing, GABAergic dysfunction, and network-level alterations; second, to leverage organoids and assembloids as next-generation platforms to investigate these processes in a human context. By integrating multi-omics, functional assays, and gene-editing tools such as CRISPR/dCas9-based epigenetic editing, researchers can uncover causal links and identify modifiable pathways. This Topic will also highlight translational approaches, including testing epigenetic drugs, validating biomarkers, and developing personalized interventions using patient-derived organoids. Ultimately, this collection seeks to unify basic mechanistic insights with human-relevant models to accelerate therapeutic innovation in AD.

We welcome contributions that explore the intersection of epigenetics and organoid-based approaches in AD and related dementias. Specific themes include, but are not limited to:

• Epigenetic mechanisms (histone modifications, DNA methylation, non-coding RNAs) in AD pathogenesis

• Organoid and assembloid models for investigating synaptic dysfunction, tauopathy, and neuroinflammation

• CRISPR-based or pharmacological epigenetic interventions tested in human-derived systems

• Multi-omics and single-cell analyses revealing regulatory networks in AD

• Biomarkers of epigenetic dysregulation and their translational potential

• Cross-disciplinary approaches integrating bioinformatics, pharmacology, and stem cell engineering

We accept a wide range of article types including Original Research, Methods, Reviews and Mini-Reviews, and Perspectives. Authors are encouraged to present pioneering findings, innovative methodologies, or integrative reviews that advance our understanding of how epigenetic pathways and organoid systems can transform AD research and therapy.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: Alzheimer’s disease; Epigenetics; Organoids; Tauopathy; Synaptic dysfunction

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.