Research Behind Stem Cell Therapy for Alzheimer's Disease

There is an extremely high rate of failure in Alzheimer’s disease (AD) drug development with 99% of trials showing no drug-placebo difference. There are many reasons why Alzheimer’s disease trials fail—among these, is the “one-drug target” paradigm. Due to the complex pathophysiology of Alzheimer’s disease, it may be necessary to take a multimodal approach to treatment. This may include incorporating drugs that target specific pathologies (e.g., amyloid and tau), stimulating endogenous neurogenesis and synaptogenesis, and neuroreplacement.

Stem cell therapy for Alzheimer’s disease represents a unique experimental method for addressing the neuroreplacement aspect of this multimodal approach. In this article, we will discuss stem cell properties and classifications and take a look at animal studies and clinical trials assessing the safety and efficacy of stem cell therapy for Alzheimer’s disease.

Stem Cell Therapy for Alzheimer’s Disease: Properties and Classifications

Stem cells have three key properties that may lend themselves well to repairing brain damage caused by neurodegenerative diseases, such as Alzheimer’s disease:

1. Stem cells are self-replicating. While most cells in the body go through a limited number of divisions before dying, stem cells are able to reproduce themselves indefinitely.
2. Stem cells are undifferentiated, meaning they don’t inherently possess specialized features associated with most cells in the body (e.g., nerves, muscle, fat, etc.).
3. Stem cells can divide and develop into many different cell types, from neurons to myocytes.

The most commonly used stem cells in Alzheimer’s disease animal and clinical research include embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and neural stem cells (NSCs). Each of these classifications comes with unique advantages and disadvantages, as detailed below.

With recent advancements in stem cell technologies and the ability to create different types of neuronal and glial cells, stem cell therapy for Alzheimer’s disease casts a new hope for Alzheimer’s treatment, providing a potential method for not only preventing further damage but for repairing and healing damage.

Stem Cell Therapy for Alzheimer’s in Animal Studies

Stem cell therapy for Alzheimer’s disease has been successful in various animal studies, including those involving ESCs, iPSCs, MSCs, and NSCs. Here’s a look at the research over the years:

• ESCs: ESCs can differentiate into neural precursor cells (NPCs) in vitro and have been transplanted into animal models of Alzheimer’s disease. In an Alzheimer’s disease rat model, mouse ESCs-derived NPCs (primed and unprimed) were transplanted in the nucleus basalis of Meynert (nbM). The Morris water maze and spatial probe test revealed a significant behavioral improvement in memory deficits following transplantation. Neither the primed nor unprimed NPCs resulted in tumor formation.

• iPSCs: iPSCs have been utilized in several AD animal models with the goal of regulating endogenous neurogenesis, reversing pathological changes, and replacing lost neurons—many of which showed promising results. One study generated iPSCs derived from mouse skin fibroblasts. After transplantation in the 5XFAD transgenic AD mouse model, protein-iPSCs differentiated into glial cells, decreasing the deposition of plaque and mitigating cognitive dysfunction. 

• MSCs: MSCs have several important potential roles in Alzheimer’s treatment. This includes immune regulation, reduction of amyloid plaque, and neuron regeneration. One study found that transplanting human adipose tissue-derived MSCs into aging mice improved both locomotor activity and cognitive function while restoring acetylcholine levels in brain tissue.

• NSCs: In mouse modes of Alzheimer’s disease, studies have shown that transplanted mouse NSCs differentiate into mature cell types within the brain and can improve several cognitive functions. One study found that transplantation of NSCs into aged transgenic mice expressing mutant presenilin, tau, and amyloid precursor protein (APP) improved spatial learning and memory function in mice with dementia without altering the amyloid or tau pathology.

Stem Cell Therapy for Alzheimer’s in Clinical Trials

While human research is still in the very early stages, clinical trials have begun assessing the safety of stem cell therapy for Alzheimer’s patients. For example, the safety and tolerability of human umbilical cord-derived MSCs (hUCB-MSCs) have been evaluated through phase I/IIa clinical trials (NCT02054208) in patients with mild to moderate Alzheimer’s disease. 

Unfortunately, there is still no evidence to suggest stem cell therapy is effective in humans. Alzheimer’s disease comes with unique challenges. Throughout the disease course, it affects multiple brain regions and many types of neurons—and it’s not yet clear if stem cells can travel to multiple brain regions and develop into each of these different types of cells. Furthermore, it is unclear if neurons derived from stem cells can effectively repair the extensive network of cell-to-cell connections that are damaged from neuronal death due to Alzheimer’s disease.

While stem cell therapy for Alzheimer’s disease may not currently represent a safe and effective method for modifying the disease course, it does represent a research space that may one day yield promising approaches for restorative therapies and/or new targets for drug development. Regardless, treatment of Alzheimer’s disease—whether through current approaches or future curative treatments—is dependent upon sufficient early diagnosis, ideally in the Mild Cognitive Impairment stage.