Stem Cell Therapies for Alzheimer Disease and Associated Challenges

Written by Isabella Castro

Edited by Moka Higashino

1 Introduction

1.1 Alzheimer’s Disease

Alzheimer’s Disease (AD) is a neurodegenerative disease which manifests with the primary symptoms of memory loss and cognitive deterioration. It is caused by the accumulation of plaques consisting of certain proteins with an incorrect secondary and/or tertiary structure (resulting in being misfolded) in the matrix surrounding neurons, as well as inflammation of neurons, tangling of neurofibrils, and loss of neurons. (Liu et al., 2020)

1.2 Stem Cell Treatments

Stem cells are cells which, like others, can self-renew, but, unlike most cells, also have the ability to differentiate into different cell types based on varying gene expression. Beyond the developmental stage of an organism, their main purpose is regenerative, making them essential to modern medical research. (Poliwoda et al., 2022)

Stem cell treatments for Alzheimer are hindered by a variety of challenges. A key area for dispute among studies is the sort of stem cell used. Options explored have included brain-derived neural stem cells, mesenchymal stem cells, and induced pluripotent stem cells, each with its own advantages and respective findings.  (Zivla, 2022).  

2 Discussion

2.1 Stem cell variety

One type of stem cell often used in AD research is brain-derived neural stem cells (NSCs). These have shown results including both differentiation into neurons and other positive effects in rodents which often function as animal models in neurological research due to the similarities between their brains and those of humans.  A study performed on Alzheimer’s disease rats found that those which had been transplanted NSCs had notably more cholinergic neurons than those which hadn’t. This type of neuron is subject to the neural loss that AD is characterized by, and is essential to the regulation of learning, attention and memory. These cognitive abilities were measured in rats using the Y-maze test, which assesses memory (spatial working and reference) as well as exploratory behavior, all of which were found to be superior in the NSC transplanted rats. (Xuan et al., 2009).

Another crucial type of stem cell in this field of research is mesenchymal stem cells (MSCs), originating from connective tissue. One study found that transplants in mice not only reduced neuroinflammation, but also inhibited tau phosphorylation, a process where phosphate groups are added to the tau protein, resulting in neurofibrillary tangles (Neves et al., 2021). A key distinction to be made for MSC’s, though, is their ability to cross the blood-brain barrier, minimizing the risk of a dangerous immune response, making them the only type of stem cell that has been used in humans rather than just animals. (Conaty et al., 2018).

A third stem cell type to be considered is induced pluripotent stem cells (iPSCs). These are derived from mature somatic cells but modified to be pluripotent (meaning they can differentiate into more types of cells), and considered an ethical alternative to embryonic stem cells (Liu et al., 2020). They are different to MSCs and NSCs because rather than being studied as a potential treatment, they are used to model cells relevant to AD. They are often derived from patients with the disease and can be differentiated into a number of cells including astrocytes, microglia, and neurons, all of which belong to the nervous system and are detrimentally affected by AD. (Sullivan & Young-Pearse 2015)

2.2 Challenges

As stem cell therapy for Alzheimer’s Disease is considered to be in the relatively early stages, there is still a multitude of obstacles to be overcome before it can be applied to real patients. Of course, there are ethical concerns regarding the sourcing of stem cells, particularly for embryonic stem cells, but alternatives have been discussed in the section above.  

A more practical concern is that of tumorigenicity. This happens due to the indefinite reproduction abilities of pluripotent stem cells, which can result in uncontrolled cell division and the presence of tumors in patients receiving stem cell transplants (Lee at al., 2013). However, this has been found to be highly dependent on the amount of stem cells transplanted to the individual. A study on immunodeficient mice found that all mice transplanted with 100000 stem cells rapidly developed tumors, whereas none of the mice transplanted with the lowest number, 100 stem cells, developed tumors. (Gropp et al., 2012)

Another concern with the practical applications of stem cell therapies is that of histocompatibility, which is the degree of compatibility between two tissues. An issue found with human stem cells used in therapies is that they present high levels of MHC-I (Major Histocompatibility Complex I), meaning the immune system of hosts recognizes them as non-self, leading to immune rejection. (Drukker et al., 2002)

3 Conclusion

Alzheimer’s disease, like many other neurological diseases, has proved challenging in research and treatment. This is due to the widespread brain damage it causes, but with modern advances in medicine and research, treatments could potentially be found and developed to reverse or at least mitigate this damage, particularly using stem cells for both their regenerative and paracrine effects.

The main disputes in research regarding this topic are about what stem cells should be used in and their associated practical obstacles. Embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, and brain derived neural cells are all options with associated ethical and practical advantages and disadvantages. As a whole though, research into each of these has shown a variety of results that, upon further investigation, could prove to be revolutionary in therapies for Alzheimer’s disease, and possibly even other similar neurological diseases.

Reference

Conaty, Peter, et al. “Methods of Mesenchymal Stem Cell Homing to the Blood-Brain Barrier.” Methods in Molecular Biology (Clifton, N.J.), vol. 1842, 2018, pp. 81–91, https://pubmed.ncbi.nlm.nih.gov/30196403/, 10.1007/978-1-4939-8697-2_6. 

Drukker, M., et al. “Characterization of the Expression of MHC Proteins in Human Embryonic Stem Cells.” Proceedings of the National Academy of Sciences, vol. 99, no. 15, 11 July 2002, pp. 9864–9869, 10.1073/pnas.142298299.

 Gropp, Michal, et al. “Standardization of the Teratoma Assay for Analysis of Pluripotency of Human ES Cells and Biosafety of Their Differentiated Progeny.” PLoS ONE, vol. 7, no. 9, 25 Sept. 2012, p. e45532, 10.1371/journal.pone.0045532.

 Lee, Andrew S., et al. “Tumorigenicity as a Clinical Hurdle for Pluripotent Stem Cell Therapies.” Nature Medicine, vol. 19, no. 8, 1 Aug. 2013, pp. 998–1004, 10.1038/nm.3267.

  Liu, Xin-Yu, et al. “Stem Cell Therapy for Alzheimer’s Disease.” World Journal of Stem Cells, vol. 12, no. 8, 26 Aug. 2020, pp. 787–802, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477654/, 10.4252/wjsc.v12.i8.787. 

 Neves, Amanda Ferreira, et al. “Intravenous Administration of Mesenchymal Stem Cells Reduces Tau Phosphorylation and Inflammation in the 3xTg-AD Mouse Model of Alzheimer’s Disease.” Experimental Neurology, vol. 341, Mar. 2021, p. 113706, 10.1016/j.expneurol.2021.113706.

 Poliwoda, Salomon, et al. “Stem Cells: A Comprehensive Review of Origins and Emerging Clinical Roles in Medical Practice.” Orthopedic Reviews, vol. 14, no. 3, 25 Aug. 2022, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9404248/, 10.52965/001c.37498. Accessed 9 July 2026.

 Sullivan, Sarah E, and Tracy L Young-Pearse. “Induced Pluripotent Stem Cells as a Discovery Tool for Alzheimer׳S Disease.” Brain Research, vol. 1656, Jan. 2017, pp. 98–106, https://pubmed.ncbi.nlm.nih.gov/26459988/, 10.1016/j.brainres.2015.10.005. 

Xuan, A G, et al. “Effects of Engrafted Neural Stem Cells in Alzheimer’s Disease Rats.” Neuroscience Letters, vol. 450, no. 2, 2009, pp. 167–71, https://pubmed.ncbi.nlm.nih.gov/19070649/, 10.1016/j.neulet.2008.12.001. 

Zivla, Eleni. “Potential and Limitations of Using Stem Cells to Cure Alzheimer’s Potential and Limitations of Using Stem Cells to Cure Alzheimer’s Disease: A Literature Review of Its Potential and Ethical Disease: A Literature Review of Its Potential and Ethical Limitations in Translation to Human Trials Limitations in Translation to Human Trials, vol. 9, 2022, p. 12, https://digitalcommons.odu.edu/cgi/viewcontent.cgi?article=1118&context=ourj, 10.25778/ddsp-3g11.