Nidhi Shah

Background: Alzheimer’s disease (AD) is a complex, multifactorial neurodegenerative disorder driven by aging, genetic predispositions, and systemic molecular dysregulation.⁴ The traditional pathogenic model highlights the extracellular deposition of amyloid-beta (Aβ) plaques and intracellular hyperphosphorylated tau tangles.^4,5 However, disease progression also involves chronic neuroinflammation mediated by microglia and severe intracellular mitochondrial dysfunction, which induce energetic failure and oxidative stress, ultimately leading to widespread synaptic loss and structural atrophy.^1,3,6 Current disease-modifying therapies, such as Aβ-based immunotherapies, present significant clinical limitations, including high costs, mixed trial successes, and severe adverse effects like microhemorrhages.^4,5 Consequently, there is an urgent need for multi-target therapies. While human stem cell transplantation offers regenerative benefits, it carries severe logistical, immunological, and biological risks.^10,11 Extracellular vesicles (EVs) offer a promising solution, functioning as biological messengers capable of actively delivering complex genetic and proteomic cargo to target cells without the invasive nature of tissue transplants.^8,10,11,12

Objective(s): The objective of this review is to evaluate the therapeutic efficacy of stem-cell-derived EVs in intercepting Alzheimer’s disease pathology at the cellular level and functionally restoring cognitive capacity.

Search Methods: A literature search of databases (e.g., PubMed) was conducted to identify relevant primary studies and reviews published between 2021 and 2026. Search terms used for the identification of literature included keywords related to “Alzheimer’s disease pathogenesis”, “stem-cell-derived extracellular vesicles”, “microglia”, and “neuroinflammation”.

Results: In vitro studies utilizing human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) exposed to toxic Aβ-42 oligomers demonstrated that EV application successfully restored mitochondrial functions.⁸ EV treatment significantly lowered markers of cell death and oxidative stress, like ROS, MDA, PCs, normalized autophagy, and reduced tau phosphorylation.⁸ In vivo models, using 5x FAD transgenic mice, showed that systemic intravenous delivery of EVs successfully reduced Aβ plaque accumulation and protected against synaptic loss.^10,11 These structural improvements directly translated to cognitive restoration, characterized by improved memory consolidation, reduced fear extinction, and significant reductions in anxiety-type behaviors.¹¹ Furthermore, EVs act as potent modulators of the central nervous system by targeting microglia.^9,11 Single-cell RNA sequencing indicated that EVs significantly reduced inflammatory transcript levels by suppressing the pro-inflammatory NLRP3 and cGAS-STING signaling cascades.⁹ Crucially, this treatment preserved microglial phagocytosis, allowing the immune cells to clear damaged Aβ and tau proteins effectively.⁹

Conclusion: Stem-cell-derived extracellular vesicles effectively target multiple mechanisms of Alzheimer’s disease neurodegeneration, achieving both pathological reduction and measurable cognitive restoration.^8,10,11 These findings suggest EVs represent a scalable, non-invasive, multi-target strategy that overcomes the limitations of live stem cell therapies.^8,9,10,11,12 Advancing this therapy toward clinical application requires further investigation into optimizing delivery routes. Non-invasive intranasal administration, which has demonstrated successful brain penetration, and mapping the distinct microRNA signatures of varying cellular lineages are the next steps for researchers to explore.^9,12 The long-term goal of EV research is the initiation and progression of human clinical trials.^8,9,10,11,12

Work Cited

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2. Bai B, Vanderwall D, Li Y, et al. Proteomic landscape of Alzheimer’s disease: novel insights into pathogenesis and biomarker discovery. Mol Neurodegener. 2021;16(1):55.
3. Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17(3):157-172.
4. Zhang J, Zhang Y, Wang J, Xia Y, Zhang J, Chen L. Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther. 2024;9(1):211.
5. Zhang Y, Chen H, Li R, Sterling K, Song W. Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future. Signal Transduct Target Ther. 2023;8(1):248.
6. D’Alessandro MCB, Kanaan S, Geller M, Praticò D, Daher JPL. Mitochondrial dysfunction in Alzheimer’s disease. Ageing Res Rev. 2025;107:102713.
7. Self WK, Holtzman DM. Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med. 2023;29(9):2187-2199.
8. Rao S, Madhu LN, Babu RS, et al. Extracellular vesicles from hiPSC-derived NSCs protect human neurons against Aβ-42 oligomers induced neurodegeneration, mitochondrial dysfunction, and tau phosphorylation. Stem Cell Res Ther. 2025;16(1):191. doi:10.1186/s13287-025-04324-3
9. Madhu LN, Kodali M, Upadhya R, et al. Extracellular vesicles from human-induced pluripotent stem cell-derived neural stem cells alleviate proinflammatory cascades within disease-associated microglia in Alzheimer’s disease. J Extracell Vesicles. 2024;13(11):e12519. doi:10.1002/jev2.12519
10. Apodaca LA, Baddour AAD, Garcia C Jr, et al. Human neural stem cell-derived extracellular vesicles mitigate hallmarks of Alzheimer’s disease. Alzheimers Res Ther. 2021;13(1):57. doi:10.1186/s13195-021-00791-x
11. Gao G, Li C, Ma Y, et al. Neural stem cell-derived extracellular vesicles mitigate Alzheimer’s disease-like phenotypes in a preclinical mouse model. Signal Transduct Target Ther. 2023;8(1):228. doi:10.1038/s41392-023-01436-1
12. Krattli RP Jr, Markarian M, Madan S, et al. Comparing functional consequences of human iPSC-microglia and neural stem cell-derived extracellular vesicles in mitigating cognitive decline in Alzheimer’s disease. Aging Cell. 2026;25(1):e70341. doi:10.1111/acel.70341