Donepezil to lecanemab-advancements in targeted therapy of Alzheimer’s disease so far
Keywords:AD, Targeted therapy, Lecanemab, Donepezil, Galantamine, Memantine
Alzheimer's disease (AD) first identified as Alois Alzheimer in 1907, is a slowly progressing dementia that affects cognition, behaviour and functional status. There is no cure for AD since precise pathophysiological mechanisms underlying it is not completely known. Drugs may temporarily reduce the symptoms associated with disorder, but condition is ultimately fatal. Objective of treatment of AD is to reduce behaviour issues associated with memory loss and improve cognition. Single acetylcholinesterase inhibitors donepezil and galantamine, as well as the dual AChE and butyrylcholinesterase (BuChE) inhibitor rivastigmine, are now utilized in treatment of AD. Cholinesterase inhibitors have shown dose-dependent impact on cognition and functional activities in clinical trials. Memantine NMDA receptor antagonist is used to minimize neurotoxicity that's suspected to contribute to conditions like Alzheimer's and other neurodegenerative disorders. Estrogen administration post menopause can result in modulation of synaptogenesis, enhanced cerebral blood flow, mediation of crucial neurotransmitters and hormones, protection against apoptosis. Aducanumab is 1st disease modifying drug and monoclonal antibody that targets beta-amyloid clusters in mild AD. Recent advancement in therapy, lecanemab, a recombinant IgG1 monoclonal antibody is targeted against aggregated soluble and insoluble forms of amyloid beta, thereby minimizing Aβ plaques and preventing Aβ deposition in the brain. As research advances, molecular basis of disease becomes more apparent leading to the advent of plausible targeted therapy.
Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, L. Michael Posey, Pharmacotherapy: A Pathophysiological Approach, 8th Edition, Alzheimer’s Disease. 2010;947-59.
Dumurgier J, Sabia S. Epidemiology of Alzheimer's disease: latest trends. Rev Prat. 2020;70(2):149-51.
Patel HH. Alzheimer's Disease Epidemiology. News-Medical. Available at: https://www.news-medical.net/health/Alzheimers-Disease-Epidemiology.aspx. Accessed on 25 March, 2023.
Kumar A, Sidhu J, Goyal A. Alzheimer Disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
Alzheimer's Disease Fact Sheet, National Institute of Aging, April 5, 2023. Available at: https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet#:~:text=As%20Alzheimer's%20worsens %2C%20people%20experience,and%20personality%20and%20behavior%20changes. Accessed on 25 March, 2023.
Symptoms and Diagnosis of Alzheimer’s Disease, National Institute of Aging, December 08, 2022, Available at: https://www.nia.nih.gov/health/how-alzheimers-disease-diagnosed. Accessed on 25 March, 2023.
Practice guideline for the treatment of patients with Alzheimer's disease and other dementias of late life. American Psychiatric Association. Am J Psychiatr. 1997;154(5):1-39.
Marucci G, Buccioni M, Ben DD, Lambertucci C, Volpini R, Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology. 2020;190.
Grossberg GT. Cholinesterase inhibitors for the treatment of Alzheimer's disease: getting on and staying on. Curr Ther Res Clin Exp. 2003;64(4):216-35.
Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet. 2002;41(10):719-39.
Dou KX, Tan MS, Tan CC. Comparative safety and effectiveness of cholinesterase inhibitors and memantine for Alzheimer’s disease: a network meta-analysis of 41 randomized controlled trials. Alz Res Therapy. 2018;10:126.
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology. 1998;50(1):136-45.
Sharma K. Cholinesterase inhibitors as Alzheimer's therapeutics. Molecular Med Rep. 2019;20:1479-87.
Jewett BE, Thapa B. Physiology, NMDA Receptor. In: StatPearls. Treasure Island (FL): StatPearls Publishing. 2023.
Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease. CNS Drug Rev. 2003;9(3):275-308.
Cacabelos R, Takeda M, Winblad B. The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease. Int J Geriatr Psychiatr. 1999;14(1):3-47.
Brianne Kuns, Alan Rosani, Memantine, Stat Pearls. 2022. Available at: https://www.statpearls.com/ ArticleLibrary/viewarticle/24945#:~:text=Memantine%20is%20an%20antagonist%20of,disease%20and%20other%20neurodegenerative%20diseases. Accessed on 25 March, 2023.
Tariot PN, Farlow MR, Grossberg GT. Memantine Treatment in Patients with Moderate to Severe Alzheimer Disease Already Receiving Donepezil: A Randomized Controlled Trial. JAMA. 2004;291(3):317-24.
Annweiler C, Karras SN, Anagnostis P, Beauchet O. Vitamin D supplements: a novel therapeutic approach for Alzheimer patients. Front Pharmacol. 2014;28;5-6.
Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo-controlled trial. Arzneimittel Forschung. 1991;41(8):773-80.
Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer's disease. Drugs. 2006;66(11):1515-34.
Altmann A, Tian L, Henderson VW, Greicius MD; Alzheimer's Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014;75(4):563-73.
Taxier LR, Philippi SM, Fleischer AW, York JM, LaDu MJ, Frick KM. APOE4 homozygote females are resistant to the beneficial effects of 17β-estradiol on memory and CA1 dendritic spine density in the EFAD mouse model of Alzheimer's disease. Neurobiol Aging. 2022;118:13-24.
Cholerton B, Gleason CE, Baker LD, Asthana S. Estrogen and Alzheimer's disease: the story so far. Drugs Aging. 2002;19(6):405-27.
Slooter AJC, Bronzova J, Witteman JCM. Estrogen use and early onset Alzheimer's disease: a population-based study. J Neurol Neurosurg Psychiatr. 1999;67:779-81.
Henderson VW. Estrogens, episodic memory, and Alzheimer's disease: a critical update. Semin Reprod Med. 2009;27(3):283-93.
Hershey LA, Lipton LB. Naproxen for pre-symptomatic Alzheimer disease. Is this the end, or shall we try again? Neurology. 2019;92(18):829-30.
John Hopkins Arthritis Center, Role of NSAIDS in Alzheimer’s Disease. Available at: https://www.hopkinsarthritis.org/arthritis-news/role-of-nsaids-in-alzheimers-disease/. Accessed on 25 March 2023.
Rivers-Auty J. Alzheimer’s Disease Neuroimaging Initiative, Anti-inflammatories in Alzheimer’s disease-potential therapy or spurious correlate? Brain Communications. 2020;2(2):fcaa109.
Zhang C, Wang Y, Wang D, Zhang J, Zhang F. NSAID Exposure and Risk of Alzheimer's Disease: An Updated Meta-Analysis From Cohort Studies. Front Aging Neurosci. 2018;10:83.
Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol Level and Statin Use in Alzheimer Disease: II. Review of Human Trials and Recommendations. Arch Neurol. 2011;68(11):1385-92.
Li Q, Chu-Na L, Jing-Long C. Statins Effects on Alzheimer’s Disease, Statins - From Lipid-Lowering Benefits to Pleiotropic Effects. Intech Open. 2023;1.
Cibičková L. Statins and their influence on brain cholesterol. J Clin Lipidol. 2011;5(5):373-9.
Masse I, Bordet R, Deplanque D, Lipid lowering agents are associated with a slower cognitive decline in Alzheimer’s disease. J Neurol Neurosur Psychiatr. 2005;76:1624-9.
Browne D, McGuinness B, Woodside JV, McKay GJ. Vitamin E and Alzheimer's disease: what do we know so far? Clin Interv Aging. 2019;14:1303-17.
Gugliandolo A, Bramanti P, Mazzon E. Role of Vitamin E in the Treatment of Alzheimer's Disease: Evidence from Animal Models. Int J Mol Sci. 2017;18(12):2504.
Dysken MW, Sano M, Asthana S. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: The TEAM-AD VA Cooperative Randomized Trial. JAMA. 2014;311(1):33-44.
Haolong L, Min Y, Hongzhu G, An Updated Review of Randomized Clinical Trials Testing the Improvement of Cognitive Function of Ginkgo biloba Extract in Healthy People and Alzheimer’s Patients, Frontiers in Pharmacol. 2020;10.
Stein C, Hopfeld J, Lau H, Klein J. Effects of Ginkgo biloba Extract EGb 761, donepezil and their combination on central cholinergic function in aged rats. J Pharm Pharm Sci. 2023;4:634-46.
Xie L, Zhu Q, Lu J. Can We Use Ginkgo biloba extract to Treat Alzheimer's Disease? Lessons from Preclinical and Clinical Studies. Cells. 2022;11(3):479.
InformedHealth.org. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006. Alzheimer's disease: Do Ginkgo products help? 2009.
Friedli MJ, Inestrosa NC. Huperzine A and Its Neuroprotective Molecular Signaling in Alzheimer's Disease. Molecules. 2021;26(21):6531.
Wang Z, Tang L, Yan H, Wang Y, Tang X. Effects of Huperzine A on Memory Deficits and Neurotrophic Factors Production after Transient Cerebral Ischemia and Reperfusion in Mice. Pharmacol Biochem. Behav. 2020;83(4):603-11.
Zhang HY, Tang XC. Neuroprotective Effects of Huperzine A: New Therapeutic Targets for Neurodegenerative Disease. Trends Pharmacol Sci. 2006;27(12):619-25.
Little JT, Walsh S, Aisen PS. An Update on Huperzine A as a Treatment for Alzheimer's Disease. Expert Opin. Investig. Drugs. 2008;17(2):209-15.
Callizot N, Campanari ML, Rouvière L, Jacquemot G, Henriques A, Garayev E, et al. Huperzia serrata Extract 'NSP01' With Neuroprotective Effects-Potential Synergies of Huperzine A and Polyphenols. Front Pharmacol. 2021;12:681532.
Yang G, Wang Y, Tian J, Liu JP. Huperzine A for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials. PLoS One. 2013;8(9):e74916.
Beshir SA, Aadithsoorya AM, Parveen A, Goh SSL, Hussain N, Menon VB. Aducanumab Therapy to Treat Alzheimer's Disease: A Narrative Review. Int J Alzheimers Dis. 2022;2022:9343514.
Aducanumab (marketed as Aduhelm) Information, U. S. Food and Drug Administration. 2021. Available at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information. Accessed on 25 March 2023.
Padda IS, Parmar M. Aducanumab. In: StatPearls. Treasure Island (FL): StatPearls. 2023.
Aducanumab Approved for Treatment of Alzheimer’s Disease, Alzhimer’s Association. Available at: https://www.alz.org/alzheimers-dementia/treatments/aducanumab. Accessed on 25 March, 2023.
Woloshin S, Kesselheim AS. What to Know About the Alzheimer Drug Aducanumab (Aduhelm). JAMA Intern Med. 2022;182(8):892.
Shi M, Chu F, Zhu F, Zhu J. Impact of Anti-amyloid-beta Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer's Disease: A Focus on Aducanumab and Lecanemab. Front Aging Neurosci. 2022;14:870517.
FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment, U. S. Food Drug Administration, 2023. Available at: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment. Accessed on 25 March 2023.
Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023;388(1):9-21.
McDade E, Cummings JL, Dhadda S. Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alz Res Therapy. 2022;14:191.