Rithi Kowtha

 Background: Alzheimer’s disease (AD) is a neurodegenerative disease marked by cognitive, functional, and behavioral impairments. AD can cause atrophy of the amygdala, substantia nigra, striatum, hypothalamus, thalamus, and various regions of the cortex.¹ The most common presentation is in elderly patients with episodic memory issues. The pathogenesis of AD involves the formation and deposition of amyloid beta (Aβ) protein.² Aβ fibrils can cause oxidative stress, neuroinflammation, and neuronal damage and death. Currently approved treatments for AD include acetylcholinesterase inhibitors and NMDA receptor antagonists, which can temporarily improve cognitive function in patients. However, current treatments are not typically administered early in disease progression, mostly due to late diagnosis. Deposition of Aβ plaques often indicates moderate-stage AD, at which point treatment may be less effective. New therapeutic candidates being investigated will target the structural foundations of the biological mechanisms behind AD, preventing disease progression from its early stages.³

Objective: This narrative review explores recent evidence on the structural and biological mechanisms of Aβ formation/elongation, aggregation, toxicity, and clearance, and evaluates how each can serve as a potential therapeutic target for AD.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2025 using the following keywords: “Alzheimer”, ” antibod*”, ” amyloid”.

Results:

Formation and Elongation – Studies of Aβ formation showed that it demonstrates a polarized, intermittent growth pattern, with random binding and dissociation of small Aβ oligomers and protofibrils. Antibody experiments using lecanemab, 6E10, 4396C, and 4G8 showed that the relative location of antibody binding on the fibril played a large role in antibody efficacy. 4396C demonstrated selective binding to the growing end of fibrils, allowing it to more directly block elongation. 6E10 and 4G8 preferentially bound to the lateral surfaces of fibrils, and thus were less effective. Lecanemab was found to stabilize smaller protofibrils and prevent their maturation into insoluble fibrils and amyloid plaques.^5,7

Aggregation – Different isoforms of apolipoprotein E (APOE) can influence Aβ aggregation and clearance. Coaggregates with lipidated apoE isoforms were much larger and more stable than their non-lipidated counterparts, facilitating their recognition and clearance by immune mechanisms. Additionally,  APOE4 gene carriers were found to have the highest levels of toxic Aβ aggregates. Thus, gene therapy for APOE4 carriers or lipidation of APOE is a treatment of interest.⁹

Toxicity – Aβ deposition was found to induce pyroptosis through activation of the caspase-1-gasdermin D (GSDMD) pathway, causing neuronal death and inflammation. Silencing of this pathway demonstrated reduced inflammation and membrane permeability. Additionally, administration of necrosulfonamide (NSA) blocked GSDMD oligomerization, protecting neurons from pyroptosis.⁶

Clearance – Aβ toxicity results in the release of inflammatory markers which recruit microglia, aiding in Aβ clearance. Studies showed that using Lecanemab to passively immunize AD diseased brains upregulated expression of microglial and lysosomal genes. This shift towards a more active clearance state increases Aβ recognition and phagocytosis.⁸

Conclusions: Studies have shown that AD progression is driven by Aβ accumulation/toxicity. Thus, therapies may be developed to various points along the Aβ pathway. Antibody treatments can be effective for inhibition of formation/elongation of toxic Aβ species , while APOE modification or gene therapy may reduce aggregation of unstable Aβ intermediates. NSA treatment can inhibit pyroptotic caspase-1-GSDMD pathway to mediate the toxic effects of Aβ. Lastly, upregulation of microglial expression via passive immunization can increase Aβ clearance.

Works Cited:

1. Kocahan S, Doğan Z. Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors. Clin Psychopharmacol Neurosci. 2017;15(1):1-8. doi:10.9758/cpn.2017.15.1.1
2. Lane CA, Hardy J, Schott JM. Alzheimer’s disease. European Journal of Neurology. 2017;25(1):59-70. doi:https://doi.org/10.1111/ene.13439
3. Porsteinsson AP, Isaacson RS, Knox S, Sabbagh MN, Rubino I. Diagnosis of early Alzheimer’s Disease: Clinical practice in 2021. The Journal of Prevention of Alzheimer’s Disease. 2021;8(3):1-16. doi:https://doi.org/10.14283/jpad.2021.23
4. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2021;384(18). doi:https://doi.org/10.1056/nejmoa2100708
5. Yagi-Utsumi M, Kanaoka Y, Miyajima S, et al. Single-Molecule Kinetic Observation of Antibody Interactions with Growing Amyloid β Fibrils. J Am Chem Soc. 2024;146(46):31518-31528. doi:10.1021/jacs.4c08841
6. Han C, Yang Y, Guan Q, et al. New mechanism of nerve injury in Alzheimer’s disease: β-amyloid-induced neuronal pyroptosis. J Cell Mol Med. 2020;24(14):8078-8090. doi:10.1111/jcmm.15439
7. Watanabe-Nakayama T, Tsuji M, Umeda K, et al. Structural Dynamics of Amyloid-β Protofibrils and Actions of Anti-Amyloid-β Antibodies as Observed by High-Speed Atomic Force Microscopy. Nano Lett. 2023;23(13):6259-6268. doi:10.1021/acs.nanolett.3c00187
8. van Olst L, Simonton B, Edwards AJ, et al. Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease. Nat Med. Published online March 6, 2025. doi:10.1038/s41591-025-03574-1
9. Xia Z, Prescott EE, Urbanek A, et al. Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease. Nat Commun. 2024;15(1):4695. Published 2024 Jun 1. doi:10.1038/s41467-024-49028-z