Pathological Mechanism of Alzheimer's Disease, Progress in Drug Development and Future Prospects

Wenzhuo Chen

doi:10.54097/epbvd190

Authors

Wenzhuo Chen

DOI:

https://doi.org/10.54097/epbvd190

Keywords:

Alzheimer disease; beta-amyloid; pathogenesis.

Abstract

Alzheimer's disease (AD) is the main cause of dementia. Its complex pathological mechanisms and multifactorial characteristics make the development of treatments face great challenges. This article reviews the origin of AD, symptom treatment drugs, pathological mechanism research, drug development progress and prevention strategies, and analyzes the limitations of current clinical applications and future development prospects. The study reviewed the historical discovery of AD, especially the genetic decoding of early-onset AD (EOAD), and explored key pathogenic genes such as APP, PSEN1, and PSEN2 and their role in the Aβ cascade hypothesis. In addition, this article summarizes the development of AD therapeutic drugs, including symptomatic treatment drugs such as cholinesterase inhibitors and memantine, as well as the progress of targeted therapy based on Aβ and Tau proteins in recent years. Although new antibody drugs such as aducanumab and lencanumab have been approved for marketing, their clinical efficacy is still controversial, and their high cost and potential side effects limit their widespread application. At present, AD research is facing the challenge of theoretical hypotheses and the exploration of new therapies. The future development direction may involve more accurate early diagnosis, biomarker screening and personalized treatment strategies, in order to improve the treatment effect and improve the quality of life of patients.

Downloads

Download data is not yet available.

References

[1] McKhann G M, Knopman D S, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[J]. Alzheimer's & dementia, 2011, 7(3): 263-269.

[2] Alzheimer’s Disease International. World Alzheimer Report[J]. 2024

[3] McKhann G M. Changing concepts of Alzheimer disease[J]. Jama, 2011, 305(23): 2458-2459.

[4] Sherrington R, Rogaev E I, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease[J]. Nature, 1995, 375(6534): 754-760.

[5] Thal L J, Rosen W, Sharpless N S, et al. Choline chloride fails to improve cognition in Alzheimer's disease[J]. Neurobiology of aging, 1981, 2(3): 205-208.

[6] Reisberg B, Doody R, Stöffler A, et al. Memantine in moderate-to-severe Alzheimer's disease[J]. New England Journal of Medicine, 2003, 348(14): 1333-1341.

[7] Corder E H, Saunders A M, Strittmatter W J, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families[J]. Science, 1993, 261(5123): 921-923.

[8] Mann D M A. The pathological association between Down syndrome and Alzheimer disease[J]. Mechanisms of ageing and development, 1988, 43(2): 99-136.

[9] Glenner G G, Wong C W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein[J]. Biochemical and biophysical research communications, 1984, 120(3): 885-890.

[10] Goldgaber D, Lerman M I, McBride O W, et al. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease[J]. Science, 1987, 235(4791): 877-880.

[11] Citron M, Oltersdorf T, Haass C, et al. Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production[J]. Nature, 1992, 360(6405): 672-674.

[12] St George-Hyslop P, Haines J, Rogaev E I, et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14[J]. Nature genetics, 1992, 2(4): 330-334.

[13] Wolfe M S, Xia W, Ostaszewski B L, et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity[J]. Nature, 1999, 398(6727): 513-517.

[14] Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus[J]. Science, 1995, 269(5226): 973-977.

[15] Hardy J A, Higgins G A. Alzheimer's disease: the amyloid cascade hypothesis[J]. Science, 1992, 256(5054): 184-185.

[16] Haass C, Selkoe D J. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide[J]. Cell, 1993, 75(6): 1039-1042.

[17] Doody R S, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease[J]. New England Journal of Medicine, 2013, 369(4): 341-350.

[18] Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse[J]. nature, 1999, 400(6740): 173-177.

[19] Nicoll J A R, Wilkinson D, Holmes C, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report[J]. Nature medicine, 2003, 9(4): 448-452.

[20] Farlow M, Arnold S E, Van Dyck C H, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease[J]. Alzheimer's & Dementia, 2012, 8(4): 261-271.

[21] Doody R S, Thomas R G, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease[J]. New England Journal of Medicine, 2014, 370(4): 311-321.

[22] Cummings J, Aisen P, Apostolova L G, et al. Aducanumab: appropriate use recommendations[J]. The journal of prevention of Alzheimer's disease, 2021, 8(4): 398-410.

[23] Cummings J, Apostolova L, Rabinovici G D, et al. Lecanemab: appropriate use recommendations[J]. The journal of prevention of Alzheimer's disease, 2023, 10(3): 362-377.

[24] Li X, Song D, Leng S X. Link between type 2 diabetes and Alzheimer’s disease: from epidemiology to mechanism and treatment[J]. Clinical interventions in aging, 2015: 549-560.

[25] Aoyagi A, Condello C, Stöhr J, et al. Aβ and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain[J]. Science translational medicine, 2019, 11(490): eaat8462.

[26] Strittmatter W J, Roses A D. Apolipoprotein E and Alzheimer's disease[J]. Annual review of neuroscience, 1996, 19(1): 53-77.

[27] Jack C R, Knopman D S, Jagust W J, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers[J]. The lancet neurology, 2013, 12(2): 207-216.

[28] Annweiler C, Rolland Y, Schott A M, et al. Higher vitamin D dietary intake is associated with lower risk of Alzheimer’s disease: a 7-year follow-up[J]. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 2012, 67(11): 1205-1211.

[29] Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease[J]. Nature Reviews Neurology, 2018, 14(11): 653-666.