The human brain is an indispensable tool for the effective translation of dementia research findings into clinical benefits. However, routine access to the living human brain for studying disease mechanisms in dementias is impossible. Although research into the molecular and neuropathological mechanisms of Alzheimer's Disease and Related Dementias (ADRD) has witnessed significant progress catalyzed by animal models, there is still a strong need for additional translational models to help identify reliable diagnostic and prognostic biomarkers and curb the extremely high failure rate of drug candidates during clinical trials. Human induced pluripotent stem cells (iPSCs) present opportunities to fully recapitulate ADRD disease mechanisms by creating brain cell types from the somatic cells of patients affected by these disorders.
Mostly, ADRD-related iPSC studies have entailed cells propagated as monolayers on flat, two-dimensional (2D) plastic or glass substrates. While these 2D modalities are quite simple to create, iPSCs cultured in these environments have been observed to display aberrant behaviors including flattened shape, abnormal polarization, loss of differentiated phenotype, and altered responses to pharmaceutical reagents. These monolayers are physiologically different from the native in vivo three-dimensional (3D) microenvironment found in the human brain. Whereas 2D iPSCs receive signals only on their ventral flat surfaces, cells in 3D cultures are able to receive signals in all three directions as present in vivo. Thus, iPSC culture systems that better recapitulate the physiological milieu are desperately needed to bridge the translational gap that occurs when extrapolating mechanisms and discoveries observed in human iPSC studies to the living human brain.

This Research Topic aims to stimulate scientific discussions around the critical need for 3D iPSC cultures as the next frontier of dementia models. Our goal is to highlight the most recent advances in the development of various architectural modalities to create 3D environments for human iPSC cultures, enabling the realization of the physiologic milieu necessary to increase the utility of human iPSCs as viable translational models of dementia.

We welcome the submission of any type of manuscript supported by the journal (original research, brief research reports, review, mini-review, methods, etc.) that mainly focuses on, but is not limited to, the following topics:
- Biocompatible hydrogels in 3D iPSC cultures
- Techniques for using hydrogels to culture iPSCs in 3D
- Techniques for culturing brain organoids and spheroids for ADRD research
- Techniques for culturing assembloids useful for ADRD investigations
- Fusions of 3D iPSC modalities with animal models to create chimeric models of ADRD
- Vascularization methods for brain organoids
- Organ-on-Chips and other engineered microphysiological systems designed to model human neurological dysfunction
- Disease mechanisms in 3D models of ADRD
- Use of 3D hydrogel cultures and organoids for ADRD drug screening
- Novel biomarkers discovery in ADRD using 3D iPSC cultures
- Ethical aspects of advanced 3D cultures

Articles accepted after peer review will be published and appear online as soon as approved for publication.

Dr. Wayne Poon is the Head of Neuroscience at Neucyte, Inc., and an inventor of patents on iPSCs-derived glial cells. No other competing interests are declared with regard to the Research Topic subject.

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Studying Dementia in 3D: Basic Techniques and Applications