Oliver Zhou

Background:  Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by buildup of amyloid-β plaques, neurofibrillary tau tangles, and neuroinflammation that leads to progressive memory loss and cognitive decline.¹ It is the most common neurodegenerative disorder and contributes to an estimated 60-80% of dementia cases worldwide.¹ It is the seventh-leading cause of death in 2021 and a leading cause of disability and morbidity in the elderly.¹ The amyloid cascade hypothesis is the classical model for AD pathogenesis and progression. It states that aggregation of insoluble amyloid-β plaques is the causative agent of hyperphosphorylated tau tangles, neuroinflammation, and neuronal destruction, hallmark findings of the AD brain.^1,2 However, more recent investigations have also revealed key roles of the immune system in AD. Microglial modifications in AD and resulting neuroinflammation have been shown to contribute significantly to neuronal death and even further formation of amyloid-β plaques and hyperphosphorylated tau tangles.² Furthermore, though it is not as well-studied, there is also literature showing that adaptive immune cells like T and B cells are dysfunctional in AD brains. The role of the immune system in the pathogenesis of AD warrants further investigation, especially with future vaccines and other potential therapies against AD in mind.

Objectives: In this narrative review, we explored the mechanisms of how immune cell dysfunction contributes to AD pathogenesis.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2023 using the following keywords: “Alzheimer’s Disease”, “innate immune system”, “adaptive immune system”, “neuroinflammation”, “microglia”, “T cell”, “B cell”

Results: The NLRP3 inflammasome was found to be required for development of tauopathy in AD mouse models. This is via a mechanism of phosphorylating kinases and phosphatases involved in tau hyperphosphorylation, including PP2A subunit C, GSK-3β, and CaMKII-α. Furthermore, NLRP3 activity was required for amyloid-β to cause tau hyperphosphorylation.³ CD4 and CD8 T cell populations were found to be abnormal in patients with AD. CD4 T cell diversity was significantly decreased in the blood of the subjects with Alzheimer’s Clinical Syndrome, suggesting clonal expansion and activation.⁴ CD8 T cells were clonally expanded as T effector memory CD45RA⁺ cells in not only the peripheral blood but also the CSF of AD patients. In the CSF, they were especially localized to the hippocampi and areas with higher amounts of amyloid-β plaques. These CD8 T_EMRA cells exhibited a proinflammatory and cytotoxic effector phenotype.⁵ B cells were also found to be required for progression of AD in a mouse model. When B cells were genetically knocked out or temporarily disabled with antibodies, mice performed better on memory tasks, had more anti-inflammatory microglia, and showed decreased amyloid-β pathology.⁶

Conclusion: The studies revealed that there are significant T cell abnormalities in human AD patients and described potential mechanisms by which the microglial inflammasome and B cells contribute to AD disease progression in mouse models. They suggest a more deeply rooted causative role of immune system dysfunction in AD pathogenesis.

Works Cited:

1. Alzheimer’s Association. 2022 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2022;18:700-789
2. 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. doi:10.1038/s41582-020-00435-y
3. Ising C, Venegas C, Zhang S, et al. NLRP3 inflammasome activation drives tau pathology. Nature. Nov 2019;575(7784):669-673. doi:10.1038/s41586-019-1769-z
4. Joshi C, Sivaprakasam K, Christley S, et al. CSF-Derived CD4(+) T-Cell Diversity Is Reduced in Patients With Alzheimer Clinical Syndrome. Neurol Neuroimmunol Neuroinflamm. Jan 2022;9(1)doi:10.1212/NXI.0000000000001106
5. Gate D, Saligrama N, Leventhal O, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature. Jan 2020;577(7790):399-404. doi:10.1038/s41586-019-1895-7
6. Kim K, Wang X, Ragonnaud E, et al. Therapeutic B-cell depletion reverses progression of Alzheimer’s disease. Nat Commun. 2021;12(1):2185. Published 2021 Apr 12. doi:10.1038/s41467-021-22479-4