The brain is one of the most essential organs that control and regulate all the critical bodily functions including maintaining the senses, voluntary or involuntary movements, behavior, emotions, and memories. Elucidating its basic growth stages and developmental mechanisms has been a major challenge for the research community over the past several decades. The increasing number of individuals with neurodegenerative as well as cognitive disorders caused by various diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) has become a major healthcare concern (Mir and Shinohara, 2013; Trojsi et al., 2018; Akula et al., 2023; Ogonah et al., 2025). Therefore, intensive research attempts are being made to dissect and investigate the developmental mechanisms of neuronal diseases or neurogenesis using advanced in vitro disease detection and modeling technologies (Mir et al., 2011; Di Lullo and Kriegstein, 2017; An et al., 2024). Toward that end, human brain organoids technology has revolutionized the field of neuroscience with their ability to mimic several aspects of the developing brain, in vitro. The remarkable three-dimensional structure of the organoid, which resembles the complexity of the human brain, offers great promise for better understanding and modeling the development of neurological diseases. Attempting to recapitulate the diversity of cell-types and cell-building organization of the embryonic human brain, researchers have successfully generated neural tissue—termed human brain organoids—using human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) (Bhaduri et al., 2020; Jacob et al., 2020; Fedorchak et al., 2021). These self-organized 3D structures continue to provide new insights into basic biology by mirroring the developmental pathways of the human brain with great accuracy (Lee et al., 2017; Zhang et al., 2022). Overall, the organoid models provide a unique opportunity to explore the physiological niches and environmental complexities of the developing human brain and to unravel the enigmatic causes behind associated abnormalities. By precisely replicating key brain structures like the midbrain, hippocampus, pituitary, hypothalamus, and cerebellum, these organoids provide an invaluable model for better understanding the mechanisms of neurodevelopmental conditions and may facilitate detailed investigation of many other unexplored pathogenetic mechanisms leading to neurodegeneration and dementia-linked disorders (Shou et al., 2020).

This review provides an overview of common neurological disorders and highlights recent progress and advancements in the field of brain organoids. In particular, it sheds light on the employment of various cell sources and emerging technologies for establishing brain organoids to more effectively reproduce the three-dimensional microenvironment of the brain. In conclusion, the current limitations and future potential of these models and their eventual translational applications are discussed.

A comprehensive search was conducted, screening through multiple databases, which included PubMed, Web of Science, and SCOPUS, and identified relevant articles published between the years 2018 and 2024. The search strategy combined Medical Subject Headings (MeSH) with text keywords using Boolean operators (OR and AND). The final search strategy developed was as follows:

(“Heredodegenerative Disorders, Nervous System”[Mesh] OR “Lewy Body Disease”[Mesh] OR “Striatonigral Degeneration”[Mesh] OR “Nerve Degeneration”[Mesh] OR “Basal Ganglia Diseases”[Mesh] OR “Frontotemporal Dementia With Motor Neuron Disease” [Supplementary Concept] OR “Corticobasal Degeneration”[Mesh] OR “Neurodegenerative Diseases”[Mesh]) OR (“Alzheimer’s*” [tw] OR AD [tw] OR “Parkinson’s*” [tw] OR Parkinsons OR “Huntington’s*” [tw] OR Huntingtons* OR “Amyotrophic lateral sclerosis” [tw] OR ALS [tw] OR “Frontotemporal dementia” [tw] OR FTD [tw] OR “Spinocerebellar degeneration” [tw] OR SCD [tw] OR “Leigh syndrome” [tw] OR “Multiple sclerosis” [tw] OR MS [tw] OR Tauopathies [tw] OR CJD [tw] OR “Creutzfeldt-jakob disease” [tw] OR Protein aggregation [tw] OR Beta amyloids [tw] OR Striatal pathways [tw] OR lewy body* [tw] OR Neuronal loss [tw] OR Impaired synaptic transmission [tw] OR Neuroinflammation [tw]) AND (Brain Organoid*) OR (3D bioprinted organoid) OR (Microfluidic organ-on-a-chip system) OR (Co-culture organoid) OR (Midbrain organoid) OR (Cerebellar organoid) OR (Spinal cord organoid) OR (Brain assembloid) AND (pathophysiology OR disease Modeling OR disease mechanisms OR pathology OR therapeutic strategies OR drug screening OR gene therapy OR limitations OR challenges).

The inclusion and exclusion criteria for this review were based on disease, intervention, and outcome parameters. Studies focusing on neurodegenerative diseases using (NDs) brain organoid models, specifically those addressing disease modeling, pathological hallmarks, functional deficits, and therapeutic interventions, were considered. Experimental studies of various types were eligible for inclusion, including randomized controlled trials, cohort studies, case-control studies, case reports, observational studies, reviews, and those with and without a control group.

Conversely, studies were excluded if they only involved cell cultures without brain organoids, focused solely on brain organoid models in animal systems, or investigated interventions unrelated to the modeling or understanding of NDs in brain organoids. Moreover, studies that lacked relevant outcome measures pertinent to NDs or that focused solely on outcomes related to non-neurological conditions were excluded.

Neurodegenerative diseases (NDs) are characterized by decreased functional activity of neurons and degeneration of neuronal cells or their terminal branches, resulting in deterioration and eventually death. These NDs are generally classified based on their characteristic symptoms, depending on the brain regions affected during the progression or gradual loss of neurons and synaptic connections. Common NDs include progressive neuropsychiatric disorders such as AD, PD, and HD, among others.

Essentially there are two distinct approaches for brain organoid generation—unguided or guided differentiation. In the unguided approach, the hPSCs are aggregated into embryoid bodies (EBs) and are then allowed to differentiate with minimal external factors or “guides” into a more heterogeneous structure called cerebral organoids. These cerebral organoids comprise different neuronal and non-neuronal cell types in proportions that do not truly mimic the natural proportions in a human brain. Also, given the differentiation process is unguided, there exists significant batch-to-batch and cell-line-to-cell-line variations limiting reproducibility and derived conclusions (Qian et al., 2019).

The guided approach, on the other hand, involves the use of growth factors and small molecules to control and direct differentiation of the EB, into specific cell-types making the resultant organoid compartment-specific, such as spinal, cortical, cerebellar, midbrain, thalamus, hippocampal, and retinal organoids (Qian et al., 2019; Zhou et al., 2024). Guided brain organoids circumvent the inconsistencies of the unguided approach and allow cell-type specific analyses.

In recent years, brain organoids have found diverse applications across scientific fields and medicinal research due to their ability to mimic brain activity and replicate physiological tissue organization. These applications have contributed to a deeper understanding of various neurological conditions and have paved the way for potential therapeutic interventions; powerful tools that serve as models for neurological disorders, offering researchers a platform to study diseases like AD, PD, and HD in a controlled environment. By simulating the development and functionality of human brains and introducing specific genetic mutations associated with these disorders into the stem cells used to generate brain organoids, these novel technologies provide valuable insights into brain function and the underlying mechanisms of various neurological disorders, helping scientists observe how aberrant genes can contribute to disease development.

Building upon the transformative capabilities of brain organoids in elucidating neurological disorders and potential therapeutic avenues, this study aims to delve deeper into the realm of utilizing brain organoids for modeling NDs. Given the evolving landscape of research surrounding these miniature brain models, this investigation seeks to address critical research questions and objectives to further enhance our understanding of disease pathology, therapeutic strategies, and the inherent limitations of brain organoid systems.

Addressing the research question regarding the current state of research on the application of brain organoids in modeling NDs, including investigations into disease pathology, therapeutic interventions, and limitations of the model systems, the particular focus of this article is on the following diseases:

Although progress has been made, challenges remain on the path to fully functional brain organoids. Aging represents a significant barrier to using hPSC-derived organoids to imitate AD, as it is one of the most important risk factors for developing AD, especially SAD. As highlighted by Bi et al., 2021, since cerebral organoids are genetically coded to be similar to fetal brains, they might not be “old” enough to accurately simulate the actual pathology observed in AD brains (Faravelli et al., 2020). Aging involves a number of genetic changes associated with the general change of the transcriptional profile of cells (Gerakis and Hetz, 2019; Papaspyropoulos et al., 2020). Another study highlights that cerebral organoids do not have the potential to generate mature neural networks, which are capable of modeling NDs. In the beginning, the organoids exhibit irregular activity, which gradually leads to a synchronous oscillatory pattern. Spatiotemporal variations complicate the network activity further as inhibitory neurons develop (Venkataraman et al., 2020). Due to biophysical constraints, brain organoids can only reach a maximal growth of about 4 mm (Matsui et al., 2018). Moreover, it has been demonstrated that despite the fact that exogenous endothelial cells can be incorporated into the brain organoids, the developing endothelial network may function inadequately (Pham et al., 2018). Faravelli et al. (2020) have also pointed out that brain organoids are deprived of structures that can provide orientation when they start differentiating.

Regardless of the guided or unguided approach, the resultant brain organoids present variations in their overall structure and size, total number of cells, extracellular matrix composition, presence of cavitation, and degree of permeability. The long-term culture duration spanning months involves the use of expensive media reagents and compounds the risk of culture contamination.

Without adequate vascularization, neuronal cell maturation is hindered due to insufficient oxygen and nutrient supply, leading to disruptions in synapse formation, also contributing to internal hypoxia and cellular stress that leads to necrosis and impaired cell subtype specification (Bhaduri et al., 2020; Papaspyropoulos et al., 2020). However, researchers have achieved vascularization by transplanting brain organoids into the rodent brain, facilitating the growth and invasion of host blood vessels into the human organoid. This breakthrough has resulted in enhanced cell survival due to effective blood perfusion, providing a glimpse into the future of organoid research (Cakir et al., 2019; Souza et al., 2023). Bi et al. (2021), in their study, also showed that the hemodynamics of the brain are closely related to Aβ production and tau phosphorylation.

The cerebral organoids produced by means of iPSCs from AD or Down Syndrome patients structurally resemble the human brain; however, they contain only neurons and glial cells—the oligodendrocytes are missing. Furthermore, active synapses are never formed in such organoids (Gonzalez et al., 2018). Despite representing many features of the human brain, even the best attempts yield underdeveloped structures and cells due to the lack of comprehensive studies on the molecular and physical evolution of the brain (Souza et al., 2023). The current AD cerebral organoids contain neurons and neuronal progenitors, which are ectoderm-derived but lack microglial cells—that play a role in the brain’s immunity in AD pathogenesis (Bi et al., 2021)—derived from the mesoderm. However, researchers propose that the creation of AD cerebral organoids with microglia can be achieved through the integration and co-culturing of various cell types, coupled with adjustments in culture formulations, thus offering potential solutions; by employing a co-culture strategy and incorporating iPSC-derived or primary human microglia into brain organoids, investigators seek to illuminate the intricate neuro-immune interactions that can either safeguard against or exacerbate neuronal pathologies (Nzou et al., 2018; Ormel et al., 2018; Song et al., 2019; Mayhew and Singhania, 2023).

While 3D organoids themselves seem to have placed a band-aid on the many limitations faced in previous models, namely, by providing better interactions between simulated brain regions, a limitation then arises that these organoids simulate only brain regions. Important organ-brain axis interactions have been shown to contribute to the development of AD. The gut-brain axis, brain-intestine kidney axis, and relations to heart health are a few examples (Kewcharoen et al., 2019; Lovell et al., 2019; Bi et al., 2021). Heart failure is significantly related to cognitive impairment, as suggested by Lovell et al. (2019) and Kewcharoen et al. (2019). Another restraint on the full feasibility of brain organoids is that they also lack any interactions with the sensory and motor systems, which are crucial for circuit maturation (Faravelli et al., 2020).

Furthermore, organoid-to-organoid and batch-to-batch discrepancies present significant challenges that can impede the reproducibility of brain organoid studies, thereby hindering high-throughput applications like drug screening. In addition, a critical obstacle in conducting extensive drug screening with cerebral organoids involves establishing dependable approaches for long-term preservation and cultivation, comparable to those employed for cell lines, while also tackling the protracted and time-intensive maturation process of organoids (Ma et al., 2022). In Table 2, we have highlighted disease-specific benefits and limitations of brain organoids in Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease.

The advent of brain organoids raises significant ethical concerns that warrant careful examination. One pressing question pertains to the potential cognitive processes and consciousness that these organoids may possess despite their miniature size (Chen et al., 2019; Koplin and Savulescu, 2019; Hyun et al., 2020; De Jongh et al., 2022). However, it is important to note that brain organoids, despite sharing some tissue composition similarities with full-sized brains, lack the necessary organization to give rise to consciousness (Chen et al., 2019; Servick, 2020; De Jongh et al., 2022). To illustrate this, we can consider a circuit kit analogy. A fully intact and properly assembled circuit kit functions flawlessly, illuminating a bulb. Conversely, if the circuit components are randomly reassembled, the individual parts may still be discernible, but the circuit will fail to activate the bulb. Similarly, while brain organoids offer insights into different brain tissue types, they cannot generate thoughts or consciousness.

Furthermore, even if brain organoids were to exhibit a more mature brain-like organization, their limited size inherently constrains their cognitive capacities (Koplin and Savulescu, 2019; De Jongh et al., 2022). A full-sized human brain consists of approximately 86 billion neurons, whereas mini-brains contain a mere fraction of that number, around 100,000 neurons (Lancaster, 2015). The intricate interconnections and elaborate networks formed by billions of neurons in the human brain are essential for enabling higher-order cognitive processes such as perception, memory, and decision-making. Regrettably, brain organoids lack the neural complexity required to support such cognitive capabilities due to their significantly reduced neuron count.

Fortunately, concerns regarding the potential for brain organoids to evolve into larger, sentient entities are unfounded. Scientists do not anticipate the growth of larger brain organoids in the foreseeable future, primarily due to the absence of blood vessels necessary for their sustenance (Lancaster, 2015; De Jongh et al., 2022). Current brain organoid cultivation typically occurs within controlled laboratory environments, inhibiting further growth and development. Without a vascular system to supply oxygen and nutrients, the expansion of brain organoids beyond their current limited size is unfeasible.

When electrical firing patterns of the brain organoids are observed, until recently the pattern was termed inconsistent and haphazard compared to adult electroencephalogram tracings. However, Trujillo et al. (2019) compared the organoids’ firing pattern development and trajectory with that of premature infants’ brains and noticed a striking similarity underlining the usefulness of these models in studying spatiotemporal organization and formation of the neural network during early human development. Although these findings may seem as getting a step closer to mimicking a human brain, the model is still very primitive given the current limitations mentioned. Also, it is imperative to remember that at a miniature scale the neuronal firing can only give us an idea of how human neural signaling works but cannot scale to the sheer complexity of the human brain in a dish, at least for now.

Another critical factor contributing to the incapability of brain organoids to exhibit higher cognitive functions lies in their inability to interact with the external world (Chen et al., 2019; Koplin and Savulescu, 2019). Interaction with the environment plays a pivotal role in human learning, as conscious thoughts and actions emerge through intricate neural networks developed via sensory feedback. From birth, our brains constantly process sensory input, enabling us to perceive, interpret, and respond to our surroundings. In contrast, brain organoids lack sensory organs, rendering them incapable of engaging in the interactive processes that shape human cognition. Consequently, brain organoids cannot form functional networks capable of exhibiting higher cognitive functions.

On a different note, when it comes to the aspect of incorporating brain organoids into the prospect of transplantations in mouse models, there have risen other ethical concerns linked with them; one in particular being the ‘humanization’ of these species (Hyun, 2016; Chen et al., 2019). According to Chen et al. (2019), it is the ethical and moral implications that arise from the generation and utilization of neural tissues that bear a growing resemblance to the human brain, which is commonly associated with the complex cognitive abilities that define our humanity. However, this proposal in the debate on brain organoid transplantation is argued by the fact that consciousness and the ‘human-like’ traits such as self-awareness, advanced cognitive capacities, and complex emotions aren’t unique to humans alone, and are shared alike by many species, whether blood runs through its system (biological species) or not (Artificial Intelligence) (Chen et al., 2019).

Introduced to the ground as the latest player, research and application rates of brain organoids have skyrocketed over the last decade, holding promise of its vast utilization in the coming years. However, to score that goal, organoids have to have instilled the value of being a team player; to be integrated with other currently growing technologies (Smirnova and Hartung, 2024).

Starting off with personalized medicine. Having patients with diverse genetic makeups, organoids developed from their iPSCs can be integrated into disease modeling, offering the possibility for individualized therapies (Smirnova and Hartung, 2024). This is so as to their ability to retain the fundamental traits of the developing brain and genetic makeup from individuals, thus garnering immense potential to lead the path toward personalized medicine for brain disorders (Koo et al., 2019).

Personalized organoids can also be vital for exploring molecular mechanisms and discovering novel diagnostic and prognostic biomarkers (Kelava and Lancaster, 2016; Koo et al., 2019). However, with personalization, drug testing also becomes a concern. With the need to test several drugs on each patient-specific disease, thousands of organoids would have to be produced. The arduousness of this task would mean that automation of the process would be an advantageous forte. Thus, enter SpinΩ, a scalable set of 3D printed mini bioreactors, a recent groundbreaking advancement enabling the simultaneous production of numerous organoids under diverse conditions, marking a significant step forward (Kelava and Lancaster, 2016). On that note, with the ability to print 3D organoids, researchers gain spatial control over the geometry and cell distribution, allowing for the mimicking of anatomically inspired structures within organoids (Koo et al., 2019; Smirnova and Hartung, 2024). To better assist the comprehension of individual heterogeneities, brain organoid biobanks could be instated; a gallery of different genetic and pathological snapshots of various patients, to aid in understanding brain disorders and supporting necessary therapeutic development as discussed above (Koo et al., 2019).

Multidimensional data generation via high-throughput imaging adds another area where technological integration can play a role. By leveraging Artificial Intelligence (AI) methods such as deep learning and machine learning, data processing can be accelerated, enabling the extraction of vital insights, classification of cell types, identification of morphological features, and detection of functional patterns (Koo et al., 2019; Smirnova and Hartung, 2024). With that, gates to a hybrid technology open; Organoid Intelligence (OI)—models that can exhibit cognition and learning (Smirnova and Hartung, 2024). Having many physiological processes difficult to perceive and thus, understand, OI systems provide a unique window into complex physiological processes, enabling direct experimental exploration of neuronal signaling and network dynamics (Smirnova and Hartung, 2024). As technological advancements progress rapidly, OI models have the potential to simulate human brain complexity by improving cell connections and myelination, promising precise representations of cognition and advanced functions alongside early proof-of-concept studies showing responsiveness to stimuli and learning abilities driven by neurophysiological adaptations (Koo et al., 2019; Smirnova and Hartung, 2024).

Concurrently, Brain-Computer Interfaces (BCIs) are also starting to rise, allowing the communication between external devices and the brain with wide applications. While primarily targeting the restoration of sensory-motor functions in cases of paralysis through brain implants, they also hold promise for enhancing memory, accessing knowledge, and enabling seamless control of technologies through thoughts. With the intertwining of organoids into this field, safer BCIs could be developed, guided by the organoids’ ability to fabricate neural structure and function (Smirnova and Hartung, 2024). Symbiotically, BCI sensors could analyze organoid activity patterns during both development and disease modeling, revolutionizing research, education, and the synergy between soul and code (Smirnova and Hartung, 2024).

Brain organoid models have proven to be invaluable tools in understanding the pathological mechanisms of major NDs like AD, PD, and HD. Their ability to replicate in vivo-like conditions enhances their potential in drug discovery and personalized medicine. However, significant limitations remain, such as the immaturity of organoids, incomplete vascularization, and the absence of significant cell types like microglia and a lack of sensory input, which impede their ability to replicate complex neural networks and age-related pathologies. Ethical concerns regarding cognitive capabilities and regarding transplanting human-like tissues into animal models deserve careful attention, especially as such procedures raise questions about the potential ‘humanization’ of other species and prompt the need for updated ethical frameworks. Despite these challenges, advancements in technology, including patient-specific organoids, automation in production, and the establishment of biobanks, hold promise for individualized therapies. Looking ahead, the integration of brain organoids with emerging technologies like SpinΩ bioreactors and 3D printing promises scalable, reproducible production, essential for high-throughput drug testing and biobank development. Combined with artificial intelligence and high-content imaging, organoids can enable more refined, multidimensional data analysis, unlocking new insights into disease mechanisms. The integration of high-throughput imaging, AI, and BCI can further enhance the utility of organoids, potentially leading to OI that simulates aspects of learning and cognition. This convergence could not only revolutionize biomedical research but also help advance neurotechnology and human-machine interactions. To fully harness the potential of brain organoids, future research should adopt a holistic approach that not only focuses on improving their complexity and addressing ethical considerations but also advances cell-type diversity, vascularization, and more dynamic brain-environment interactions through strong interdisciplinary collaboration to overcome existing barriers.