Julie Hill-Mak

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline affecting language comprehension, executive function, spatial cognition, and memory recall.¹ AD is the leading cause of dementia worldwide, with an estimated 50 million people affected, a number expected to rise significantly by 2050.² Known risk factors include genetics, age over 65, cardiovascular diseases, hypertension, hyperlipidemia, midlife obesity, diabetes, and biological sex.² Mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), presenilin-2 (PSEN-2), SHANK-associated RH domain-interacting protein (SHARPIN), and apolipoprotein E (ApoE) are associated with AD.¹ The development of Alzheimer’s disease is believed to advance as Aβ oligomers accumulate to form plaques.¹ The immune system, particularly microglial cells facilitating phagocytosis, plays a crucial role in AD pathogenesis.³ While management techniques aim to slow symptom progression, there is currently no cure for Alzheimer’s Disease.

Objective: The connection between Aβ plaque buildup and neuronal dysfunction in AD progression is incomplete. Investigating these pathways can provide crucial insights for potential treatment options. This review aims to investigate how dysregulated Aβ plaque production can be cleared through microglial phagocytosis, especially with the application of antibody therapy such as Donanemab.

Search Methods: An online PubMed database search was conducted for articles from 2019 to 2024 using the keywords: “Alzheimer’s disease”, “microglial phagocytosis”, and “antibody therapy”.

Results: A rare functional variant of SHARPIN, rs572750141 (G186R), is significantly associated with AD due to its impact on the NF-κB pathway, which regulates neuroinflammation, amyloid-β (Aβ) production, and neuronal survival.^4,5 Introducing this variant into HEK293 cells showed reduced activation of the NF-κB pathway and increased secretion levels of Aβ 40 and 42.⁵ Donanemab, an immunoglobulin G1 monoclonal antibody, targets a specific form of Aβ found exclusively in brain amyloid plaques, and facilitates plaque removal through microglial-mediated phagocytosis.⁶ This is particularly relevant in patients with mutations like SHARPIN, where their ability to initiate a phagocytic response is compromised.^4,5 The efficacy of Donanemab was evaluated in an 18-month, randomized, double-blind, placebo-controlled, phase 3 trial involving 8 hospitals and 277 medical research centers with 1736 patients aged 60 to 85.⁶ The patients were separated into two groups: low/medium tau pathology or combined (low/medium and high) tau pathology. At 24 weeks, 34.2% of Donanemab-treated participants in the low/medium tau population achieved amyloid clearance, increasing to 80.1% of the population by the end of the 76-week trial.⁶ In the combined population, amyloid clearance occurred in 29.7% of Donanemab-treated participants at 24 weeks and 76.4% at 76 weeks, compared to negligible clearance in the placebo group.⁶ Additionally, there was notable improvement in cognition, reflected by improved iADRS scores.⁶

Conclusion: Understanding connections between Aβ plaque buildup and neuronal dysfunction in AD is crucial for potential treatment strategies. Significant amyloid clearance via microglial phagocytosis and cognitive improvement in participants treated with Donanemab were observed in clinical trials. In the future, investigating the role of SHARPIN and the efficacy of antibody therapy could provide essential insights into AD pathogenesis and offer treatment avenues, ultimately improving care for those affected by the disease.

Works Cited:

1.  Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Molecules. 2020;25(24):5789. Published 2020 Dec 8. doi:10.3390/molecules25245789
2. Zhang XX, Tian Y, Wang ZT, Ma YH, Tan L, Yu The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention. J Prev Alzheimers Dis. 2021;8(3):313-321. doi:10.14283/jpad.2021.15
3. Schedin-Weiss S, Nilsson P, Sandebring-Matton A, et al. Proteomics Time-Course Study of App Knock-In Mice Reveals Novel Presymptomatic Aβ42-Induced Pathways to Alzheimer’s Disease Pathology. J Alzheimers Dis. 2020;75(1):321-335. doi:10.3233/JAD-200028
4. Liu, T., Zhang, L., Joo, D. et al. NF-κB signaling in inflammation. Sig Transduct Target Ther 2, 17023 (2017). https://doi.org/10.1038/sigtrans.2017.23
5. Asanomi Y, Kimura T, Shimoda N, Shigemizu D, Niida S, Ozaki K. CRISPR/Cas9-mediated knock-in cells of the late-onset Alzheimer’s disease-risk variant, SHARPIN G186R, reveal reduced NF-κB pathway and accelerated Aβ secretion. J Hum Genet. Published online February 13, 2024. doi:10.1038/s10038-024-01224-x
6. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239