Systematic Overview: AD Pathology and Recent Pharmacological Advances

Tingxi Luo

doi:10.62051/sp72fq46

Authors

Tingxi Luo

DOI:

https://doi.org/10.62051/sp72fq46

Keywords:

Alzheimer’s disease; Amyloid-β; Tau; Aducanumab.

Abstract

This systematic review provides a comprehensive analysis of Alzheimer’s Disease (AD) pathology and its pharmacological advancements. Population aging over last decades render AD becoming more prevalent, indicating a significant sociological and economic burden. Yet, due to the complexity of the brain structure, the researchers must understand AD’s multifactorial pathology and progression mechanisms in order to find an effective treatment. The review will primarily examine the classical amyloid-β hypothesis and tau protein’s involvement, exploring their interplay in neuronal degeneration. Additionally, it also examines the emerging theories of neuroinflammation, prion-like proteins and vascular damages as crucial contributors to AD pathology. Recently, several FDA-approved non-curative drugs have been reported to reduce amyloid-β plaque and/or enhance cognitive function. Consequently, beyond analyzing AD’s pathological hypotheses, critically assessments on recent pharmacological advances using monoclonal antibodies (Aducanumab), cholinesterase inhibitors (Donepezil) and NMDA antagonists (Memantine) are used as examples to compare their clinical efficacies and controversies. Discussion on other factors including ethical considerations, personalized medicine and the transformation of treatment paradigms are included. By identifying a paradigm shift towards a multi-targeted approach which integrates pharmacological and non-pharmacological interventions, this review underscores the necessities of ethical concerns and patient-centred treatments. Thus, this review aims to present an academic consolidation of current knowledge and stimulate further interdisciplinary research, promoting innovation in AD treatment.

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References

Alonso, A.D., Cohen, L.S., Corbo, C., Morozova, V., ElIdrissi, A., Phillips, G. and Kleiman, F.E. Hyperphosphorylation of Tau Associates with Changes in Its Function beyond Microtubule Stability. Frontiers in Cellular Neuroscience, 2018, 12.

Birks, J.S. and Harvey, R.J. Donepezil for Dementia Due to Alzheimer’s Disease. Cochrane Database of Systematic Reviews, 2018, 2 (6).

Breijyeh, Z. and Karaman, R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 2020, 25 (24), p.5789.

Chen, G., Xu, T., Yan, Y., Zhou, Y., Jiang, Y., Melcher, K. and Xu, H.E. Amyloid beta: structure, Biology and structure-based Therapeutic Development. Acta Pharmacologica Sinica, 2017, 38 (9), pp.1205 – 1235.

Haddad, H.W., Malone, G.W., Comardelle, N.J., Degueure, A.E., Kaye, A.M. and Kaye, A.D. Aducanumab, a Novel Anti-Amyloid Monoclonal Antibody, for the Treatment of Alzheimer’s Disease: A Comprehensive Review. Health Psychology Research, 2022, 10 (1).

Heneka, M.T., Golenbock, D.T. and Latz, E. Innate Immunity in Alzheimer’s Disease. Nature Immunology, 2015, 16 (3), pp.229 – 236.

Iqbal, K., Liu, F. and Gong, C.-X. Tau and Neurodegenerative disease: the Story so Far. Nature Reviews Neurology, 2015, 12 (1), pp.15 – 27.

Jack, C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., Petersen, R.C. and Trojanowski, J.Q. Hypothetical model of dynamic Biomarkers of the Alzheimer’s pathological cascade. The Lancet Neurology, 2010, 9 (1), pp.119 – 128.

Liddelow, S.A., Guttenplan, K.A., Clarke, L.E., et al. Neurotoxic Reactive Astrocytes Are Induced by Activated Microglia. Nature, 2017, 541 (7638), pp.481 – 487.

McShane, R., Westby, M.J., et, al. Memantine for Dementia. Cochrane Database of Systematic Reviews, 2019, 3(3).

Richard, Armstrong.A. Risk Factors for Alzheimer’s Disease. Folia Neuropathologica, 2019, 57 (2), pp.87 – 105.

Sierksma, A., Lu, A., Mancuso, R., Fattorelli, N., et al. Novel Alzheimer Risk Genes Determine the Microglia Response to Amyloid‐β but Not to TAU Pathology. EMBO Molecular Medicine, 2020, 12 (3).

Vaz, M., Silva, V., Monteiro, C. and Silvestre, S. Role of Aducanumab in the Treatment of Alzheimer’s Disease: Challenges and Opportunities. Clinical Interventions in Aging, 2022, Volume 17, pp.797 – 810.

Watts, J.C. and Prusiner, S.B. (7). β-Amyloid Prions and the Pathobiology of Alzheimer’s Disease. Cold Spring Harbor Perspectives in Medicine, 201, 8 (5), p.a023507.

Yoon, S.-S. and AhnJo, S.-M. Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer’s Disease. Biomolecules and Therapeutics, 2012, 20 (3), pp.245 – 255.

Zenaro, E., Piacentino, G. and Constantin, G. The blood-brain Barrier in Alzheimer’s Disease. Neurobiology of Disease, 2017, 107, pp.41 – 56.

Zhang, C., Browne, A., DiVito, J.R., Stevenson, J.A., Romano, D., Dong, Y., Xie, Z. and Tanzi, R.E. Amyloid-β Production via Cleavage of Amyloid-β Protein Precursor Is Modulated by Cell Density. Journal of Alzheimer’s Disease, 2010, 22 (2), pp.683 – 984.

Zhang, Y., Thompson, R., Zhang, H. and Xu, H. APP Processing in Alzheimer’s Disease. Molecular Brain, 2011, 4 (1), p.3.