Alzheimer’s disease (AD) is the most common cause of dementia, gradually destroying memory, learning, and functional independence. Current FDA-approved drugs such as donepezil, rivastigmine, galantamine, and memantine provide limited symptomatic relief but do not slow the progression of neuronal loss. Antibody therapies that target amyloid plaques have shown inconsistent clinical outcomes. As a result, researchers are pursuing biological therapies that act on multiple disease pathways simultaneously. Mesenchymal stem/stromal cells (MSCs) are one of the most promising candidates under investigation.
As part of this review, Regmi et al. focus on different clinical and preclinical studies using MSC as a therapy for treating AD, their outcomes, limitations and the strategies to potentiate their clinical translation.
Disease Progression and Pathophysiology
AD develops slowly, progressing from a preclinical phase with no visible symptoms to mild cognitive impairment and eventually to dementia. Early in the disease, abnormal accumulation of amyloid-beta and metabolic dysfunction begin to disrupt neuronal communication. Over time, inflammation, oxidative stress, and tau protein abnormalities lead to widespread neuronal death. Most cases are diagnosed after age 65 (late-onset AD), while a smaller number of familial and early-onset forms appear earlier and are often linked to genetic mutations in the amyloid precursor protein or presenilin genes.
Rationale for Stem Cell Therapy
Stem cell-based interventions aim to repair or protect the brain rather than simply alleviate symptoms. By influencing cellular and immune processes, stem cells have the potential to address core mechanisms of AD, including inflammation, oxidative injury, and synaptic loss. Mesenchymal stem/stromal cells are particularly attractive because they are relatively easy to obtain from bone marrow, adipose tissue, or umbilical cord sources. They have low immunogenicity, strong anti-inflammatory and regenerative potential, and do not present the ethical or oncogenic risks associated with embryonic stem cells.
Mechanisms of Action of Mesenchymal Stem Cells
MSCs exert therapeutic effects primarily through their secreted factors rather than direct cell replacement. They release a complex mixture of cytokines, growth factors, and microRNAs that modulate inflammation, promote neuronal survival, and enhance the brain’s self-repair mechanisms. Key mechanisms include the suppression of pro-inflammatory immune responses, stimulation of microglial clearance of amyloid-beta, reduction of tau hyperphosphorylation, and protection of neurons from oxidative and apoptotic stress. MSCs also secrete neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), which support neurogenesis and synaptic plasticity.
Evidence from Preclinical Research
In animal models of AD, MSC transplantation has consistently reduced amyloid burden, decreased inflammation, and improved cognitive performance. Studies using MSCs from bone marrow, adipose tissue, placenta, and umbilical cord sources have demonstrated enhanced memory retention, reduced oxidative stress, and improved neural connectivity. The therapeutic mechanism appears to vary with disease stage: in early disease, MSCs enhance amyloid clearance and regulate tau processing; in later stages, their effects are more strongly associated with antioxidant and anti-inflammatory actions.
Findings from Clinical Trials
Early human trials suggest that MSC therapy is safe and feasible. Patients receiving MSCs through intracerebral, intravenous, or intrathecal routes have generally tolerated treatment without serious adverse effects. Some studies have shown modest improvements in cognitive function and inflammatory biomarkers, while others report minimal change. The variation in results likely reflects differences in cell source, dose, route of administration, and disease stage. Continued large-scale, standardized clinical studies are needed to determine optimal protocols and confirm therapeutic efficacy.
Role of MSC-Derived Exosomes and Extracellular Vesicles
Much of the therapeutic activity of MSCs is now attributed to the extracellular vesicles (EVs) they release. These nanoscale structures, including exosomes, contain proteins, enzymes, and microRNAs capable of crossing the blood-brain barrier. EVs can replicate many of the beneficial effects of MSCs while minimizing risks such as immune rejection or tumor formation. Research has shown that MSC-derived exosomes can reduce amyloid-beta levels, suppress inflammation, and improve cognitive outcomes in AD models. MicroRNAs such as miR-21, miR-29b, miR-29c-3p, and miR-455-3p appear to regulate pathways that protect neurons, clear toxic proteins, and enhance synaptic health.
Regulation of Microglial Function
According to the authors, microglia play a dual role in the AD brain—clearing debris and pathogens under normal conditions but driving chronic inflammation when persistently activated. MSCs help reprogram microglia toward a neuroprotective, anti-inflammatory phenotype. They secrete molecules such as soluble intercellular adhesion molecule-1 (sICAM-1), CX3CL1, and growth differentiation factor-15 (GDF-15) that enhance the clearance of amyloid-beta and suppress pro-inflammatory cytokines. By promoting a balance between microglial activation and resolution, MSCs reduce oxidative stress and protect surrounding neurons from further injury.
Challenges in Clinical Translation
Despite encouraging findings, MSC-based therapy faces several technical and biological challenges. Intravenously delivered MSCs are often trapped in the lungs, limiting brain exposure. The blood-brain barrier restricts cell migration, and outcomes vary based on patient age, disease severity, and individual immune responses. Standardization across studies remains a critical barrier: cell sources, preparation methods, and dosing regimens differ widely. Consistent, reproducible manufacturing practices are necessary for large-scale clinical application.
Emerging Strategies to Enhance Efficacy
Researchers are exploring innovative approaches to overcome delivery and efficacy challenges. Direct injection into brain tissue or cerebrospinal fluid can increase local concentrations of MSCs, while focused ultrasound can temporarily open the blood-brain barrier to facilitate targeted delivery. Magnetic targeting using nanoparticle-labeled MSCs and external magnets may also improve cell homing. Preconditioning MSCs with agents such as melatonin or cannabidiol enhances their survival and therapeutic potency. Genetic engineering approaches are being tested to overexpress beneficial molecules such as BDNF, VEGF, and Wnt3a. In parallel, MSC-derived exosomes are being developed as a cell-free therapeutic platform, combining many of the benefits of MSCs with improved safety and scalability.
Matching Therapy to Disease Stage
Treatment effectiveness may depend on when MSCs are introduced. Early in the disease, the goal is to enhance clearance of amyloid and preserve synapses, whereas in later stages the focus shifts toward reducing inflammation, protecting surviving neurons, and maintaining cognitive function. Regmi et al. report that future clinical protocols will likely tailor treatment approaches to biomarkers and disease progression to maximize benefit for individual patients.
Current Clinical Considerations
MSCs for Alzheimer’s disease remain in the experimental phase. Early studies indicate safety and biological activity, but definitive evidence of long-term clinical benefit is lacking. Patients considering participation in MSC trials should ensure that studies are properly regulated and that the source, preparation, and administration of cells or exosomes are clearly described. Understanding how the intervention aligns with individual disease stage and biomarkers is essential to setting realistic expectations.
Future Directions and Outlook
Mesenchymal stem/stromal cells represent a multifaceted therapeutic avenue for Alzheimer’s disease, addressing inflammation, oxidative damage, neuronal loss, and vascular dysfunction simultaneously.
According to the authors, the next phase of research must focus on standardizing cell preparation, identifying optimal delivery routes, and designing rigorous, well-powered clinical trials. Continued advances in focused ultrasound, genetic enhancement, and exosome technology are expected to strengthen the feasibility and impact of this approach.
Advancing Toward Clinical Application
Although mesenchymal stem cell therapy is not yet a proven treatment for Alzheimer’s disease, the authors indicate that the growing body of preclinical and early clinical evidence suggests significant therapeutic promise. By promoting neuroprotection, immune regulation, and tissue repair, MSCs and their derivatives could form the foundation of next-generation regenerative strategies for neurodegenerative conditions.
With further research and careful clinical translation, MSC-based therapies may one day help preserve cognitive function and improve quality of life for individuals affected by Alzheimer’s disease.
Source: Regmi S, Liu DD, Shen M, Kevadiya BD, Ganguly A, Primavera R, Chetty S, Yarani R, Thakor AS. Mesenchymal stromal cells for the treatment of Alzheimer’s disease: Strategies and limitations. Front Mol Neurosci. 2022 Oct 6;15:1011225. doi: 10.3389/fnmol.2022.1011225. PMID: 36277497; PMCID: PMC9584646.
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