Lecanemab: A New Horizon in Alzheimer’s Disease Treatment

Written by: Maryam Isayeva

Edited by: Ray Zhang and Shivani Patel

Illustrated by: Toni Chavez

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Introduction

Alzheimer’s disease is one of the most prevalent neurodegenerative diseases of the 21st century, with symptoms including memory problems, trouble finding the right word during a conversation, difficulty comprehending visual images and diagrams, as well as impaired judgment or reasoning. Although the disease manifests differently across patients, symptoms typically worsen as the disease progresses [1]. As of 2023, about 6.7 million people in the US are affected by the disease, with the number estimated to reach 14 million by 2060 [2]. Although there is currently no known cure for Alzheimer's, despite its high prevalence and number of cases highlighting the dire need for effective treatments, the emergence of a new drug called Lecanemab offers a promising beacon of hope for the millions suffering from the disease [3]. The novel drug, developed by pharmaceutical companies Eisai and Biogen, targets the pathology of Alzheimer’s and is the first medication against Alzheimer’s to be approved by the FDA in more than two decades [4]. So, how does it work?

How Lecanemab Targets Alzheimer’s Pathophysiology

In order to understand the mechanisms underlying Lecanemab, it is first necessary to go through the pathophysiology of Alzheimer’s and the causes of this disease. The current belief, supported by decades of research, suggests that Alzheimer’s disease (AD) is a result of the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain; however, the specific cause of the disease remains to be identified [5]. Beta-amyloid is a fragment of the larger amyloid precursor protein (APP), which is known to play an important role in neural growth and maturation during brain development [6]. Meanwhile, abnormal accumulations of the tau protein, responsible for stabilizing microtubules that maintain cell shape and transport of materials in the cell, create so-called neurofibrillary tangles within neurons [7]. This prevents neurons from being able to communicate with each other properly. It isn’t known whether beta-amyloid and tau proteins are harmful or merely a side effect of Alzheimer’s. However, in a healthy human brain, these beta-amyloid and tau protein fragments appear harmless as they are not able to accumulate—they are broken down and eliminated, causing no damage to the brain and its neurons, which are nerve cells all around the body that send messages from the body to the brain and vice versa [8].

Neurons are what allow us to do daily activities such as breathing, walking, eating, and thinking. These cells communicate with each other through gaps between two neurons called synapses [9]. Alzheimer’s is often characterized by plaques, an accumulation of the beta-amyloid and tau proteins in clumps, between neurons in these synapses [10].  This formation of plaques and tangles between neurons disrupts the process of transmitting information, causing the loss of neuron function and, over time, the loss of brain tissue and cognitive function deterioration often witnessed in AD patients [11]. While the reason behind why beta-amyloid plaques form is still unknown, the presence of these plaques is a primary feature of Alzheimer’s pathophysiology, and this is the area often targeted by prospective treatments [6].

Since Lecanemab is a monoclonal antibody, a molecule produced in laboratories that can mimic the immune system’s ability to fight off specific harmful substances in the body, it is able to treat Alzheimer’s by targeting beta-amyloid plaques, recognizing and binding to them [12]. However, the drug itself does not remove these clumps; instead, Lecanemab flags the protein plaques as soon as it is attached to them, functioning as a sign for the immune system to now clear these fragments from the brain, just like a healthy human brain would [13]. This procedure has two effects: first, it may reduce the formation of new plaques in the brain, and second, it may be able to recognize and flag existing them for clearance, reducing their impact on the surrounding neurons. Lecanemab is believed to slow down the progression of AD, preserving some neurons and therefore, preserving cognitive functions [14]. 

Advantages of the Drug

One of the most persuasive arguments for the use of Lecanemab is its success in Phase 3 trials, which is what gained the drug its FDA approval. Researchers design Phase Three studies to demonstrate whether or not a product offers a treatment benefit to a specific population [15]. Research and clinical trials have shown that the biweekly administration of Lecanemab in early-stage Alzheimer’s patients resulted in a notable decrease in the presence of beta-amyloid plaques and subsequent deceleration of cognitive function deterioration. Furthermore, the results indicated that the drug has a positive effect on slowing down Alzheimer’s progression [16]. 

Moreover, Lecanemab stands out from other types of similar drugs due to its ability to treat the neurological changes associated with the disease rather than attempt to mitigate the symptoms. The general standard of treatment for Alzheimer’s revolves around symptom management rather than treating the cause [17]. These drugs are aimed at improving cognitive function and alleviating certain behavioral symptoms, such as aggression and agitation, without treating the root of the problem. On the other hand, Lecanemab targets a possible root of the problem by reducing the accumulation of the plaques [16].

Another important advantage of the drug is its positive impact on patients and their families. As mentioned before, Alzheimer’s is characterized by a decline in cognitive functions which is strenuous both for the patient as well as for their friends and family. By slowing down the progression of the disease, Lecanemab improves the quality of life for the patient while giving their loved ones more time with them [18]. This could reduce caregiver burden, as well as relieve some of the financial burdens associated with caring for AD patients [19]. 

Disadvantages

Every drug has side effects, and Lecanameb is no exception. The most common side effect associated with the treatment is Amyloid-Related Imaging Abnormalities, known as ARIA [20]. These abnormalities are seen on brain-imaging MRI scans and often present either as ARIA-Edema (E), swelling in the brain, or as ARIA-Hemorrhage (H), small bleeds or hemorrhages in the brain [21]. While ARIA is not always symptomatic, it is still a concern as it may progress and cause discomfort and pain for the patient. Other side effects of Lecanemab include headaches and fatigue, as well as infusion-related reactions, such as shivering, nausea, or blood pressure variations [22]. Since there are no similar drugs, it is impossible to compare the side effects caused by Lecanemab to a standard, but it is still important to note them. 

Another critical disadvantage of Lecanmab is its limited use—it is only effective for patients with early-stage Alzheimer’s. The drug is not a cure, it is a treatment. Therefore, its efficacy is directly related to the stage of a patient’s Alzheimer’s [23]. The disease starts in the preclinical stage, at which point it is asymptomatic - the changes in the brain may only be seen through neuroimaging. The disease then progressed to the mild, early stage, characterized by insignificant memory problems that do not interfere with a person’s ability to live independently. At that point, Lecanemab may be introduced as a potential treatment. The third stage, the moderate middle stage, is marked by more severe memory deficiencies, preventing the patient from conducting daily activities without help. The final stage of Alzheimer’s, the late stage, is known to impair the individual’s ability to do any activity significantly, and those patients typically require full-time assistance [24]. 

The reason why the drug is effective in the early mild stages of Alzheimer’s is that the presence of amyloid plaques has not yet caused significant neurological damage and brain atrophy—allowing the drug to slow down Alzheimer’s progression [25]. However, as the disease progresses, brain atrophy takes place, which renders the removal of plaques ineffective—the surrounding neurons are already dead—and there is no more cognitive function relevant to the area to be preserved. Clinical trial evidence has also shown the deceleration of cognitive deterioration is only applicable in patients in the mild stages of AD [26]. Consequently, the use of Lecanemab is restricted only to a specific patient population, as the benefit in the later stages of the disease is highly limited. That being said, Lecanemab has shown significant positive efficacy in patients with early Alzheimer’s. A large study named Clarity AD demonstrated that the group treated with Lecanemab showed a 27% reduction in clinical decline in the accumulation of plaques compared to the placebo group, demonstrating the drug's effectiveness despite its novelty [27].

However, Lecanemab is not entirely accessible even to the population that may benefit from it due to its high costs. The drug has to be administered every two weeks intravenously for it to have an effect, with the recommended treatment lasting around 18 months, and the annual cost per patient of the drug alone is about $26,500 which does not include all other associated expenses, such as assisted living and caregiver support [28-29]. The total cost may come to somewhere around $82,500 per year [30]. This is not a low cost, and the price tag for Lecanemab must be considered in addressing its accessibility and affordability to patients. Some insurance companies, such as Medicare, have recently begun to cover the drug; however, that is not the case in every state and country [31]. Despite this, Lecanemab still appears to be one of the most promising drugs on the market for treating Alzheimer’s. 

Considerations and Conclusions 

To truly understand the importance of Lecanemab’s role in the treatment of Alzheimer’s, it is also crucial to recognize the significance of the early detection of the disease through the use of neuroimaging [32]. This is due to the fact that the effectiveness of Lecanemab hinges upon catching Alzheimer’s in its early stages which underlines the importance of screening. This necessity points to a larger issue within the American healthcare system: the urgent need for better access to diagnostic services, especially for individuals at higher risk, to start Lecanemab treatment promptly. In addition to that, the cost of the drug presents another hurdle to accessible treatment.

Lecanemab is gaining ground worldwide, with its recent government approval in places like Japan showcasing strides in the global battle against Alzheimer's [28]. This international nod to its potential is making it easier for healthcare systems around the world to start using it. This growth in the drug's acceptance is fueling a more optimistic outlook in Alzheimer’s research, promising better care and improved outcomes for patients everywhere.

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References

[1] National Institute on Aging. "What Are the Signs of Alzheimer's Disease?" National Institute on Aging, U.S. Department of Health & Human Services, 18 Oct. 2022, www.nia.nih.gov/health/alzheimers-symptoms-and-diagnosis/what-are-signs-alzheimers-disease

[2] Centers for Disease Control and Prevention. "About Alzheimer's Disease." Centers for Disease Control and Prevention, U.S. Department of Health & Human Services, 12 Apr. 2023, www.cdc.gov/aging/alzheimers-disease-dementia/about-alzheimers.html 

[3] National Institute on Aging. "How Is Alzheimer's Disease Treated?" National Institute on Aging, U.S. Department of Health & Human Services, 12 Sep. 2023, www.nia.nih.gov/health/alzheimers-treatment/how-alzheimers-disease-treated

[4] MacMillan, Carrie. "Lecanemab, the New Alzheimer’s Treatment: 3 Things To Know." Yale Medicine, 24 July 2023, www.yalemedicine.org/news/lecanemab-leqembi-new-alzheimers-drug

[5] Yarns, Brandon C et al. “Pathophysiology of Alzheimer's Disease.” The Psychiatric clinics of North America vol. 45,4 (2022): 663-676. doi:10.1016/j.psc.2022.07.003

[6] Murphy, M Paul, and Harry LeVine 3rd. “Alzheimer's disease and the amyloid-beta peptide.” Journal of Alzheimer's disease : JAD vol. 19,1 (2010): 311-23. doi:10.3233/JAD-2010-1221

[7] National Institute on Aging. "What Happens to the Brain in Alzheimer's Disease?" National Institute on Aging, U.S. Department of Health & Human Services, 19 Jan. 2024, www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/what-happens-brain-alzheimers-disease

[8] Reiss, Allison B et al. “Amyloid toxicity in Alzheimer's disease.” Reviews in the neurosciences vol. 29,6 (2018): 613-627. doi:10.1515/revneuro-2017-0063

[9] Ludwig, Parker E., et al. “Neuroanatomy, Neurons.” StatPearls, StatPearls Publishing, 24 July 2023.

[10] Gouras, Gunnar K et al. “β-Amyloid peptides and amyloid plaques in Alzheimer's disease.” Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics vol. 12,1 (2015): 3-11. doi:10.1007/s13311-014-0313-y

[11] Siddappaji, Kiran Kumar, and Shubha Gopal. “Molecular mechanisms in Alzheimer's disease and the impact of physical exercise with advancements in therapeutic approaches.” AIMS neuroscience vol. 8,3 357-389. 19 Mar. 2021, doi:10.3934/Neuroscience.2021020

[12] Cleveland Clinic. "Monoclonal Antibodies: Definition & How Treatment Works." Cleveland Clinic, 16 Nov. 2021, www.clevelandclinic.org/health/treatments/22246-monoclonal-antibodies

[13] Knopman, David S. “Lecanemab reduces brain amyloid-β and delays cognitive worsening.” Cell reports. Medicine vol. 4,3 (2023): 100982. doi:10.1016/j.xcrm.2023.100982

[14] Wright, Abigail C et al. “The effectiveness and value of lecanemab for early Alzheimer disease: A summary from the Institute for Clinical and Economic Review's California Technology Assessment Forum.” Journal of managed care & specialty pharmacy vol. 29,9 (2023): 1078-1083. doi:10.18553/jmcp.2023.29.9.1078

[15] U.S. Food and Drug Administration. "Step 3: Clinical Research." FDA, U.S. Department of Health & Human Services, 1 Apr. 2018, www.fda.gov/patients/drug-development-process/step-3-clinical-research

[16] Chowdhury, Selia, and Nurjahan Shipa Chowdhury. “Novel anti-amyloid-beta (Aβ) monoclonal antibody lecanemab for Alzheimer's disease: A systematic review.” International journal of immunopathology and pharmacology vol. 37 (2023): 3946320231209839. doi:10.1177/03946320231209839

[17] Yiannopoulou, Konstantina G, and Sokratis G Papageorgiou. “Current and Future Treatments in Alzheimer Disease: An Update.” Journal of central nervous system disease vol. 12 1179573520907397. 29 Feb. 2020, doi:10.1177/1179573520907397

[18] Tahami Monfared, Amir Abbas et al. “Long-Term Health Outcomes of Lecanemab in Patients with Early Alzheimer's Disease Using Simulation Modeling.” Neurology and therapy vol. 11,2 (2022): 863-880. doi:10.1007/s40120-022-00350-y

[19] Reed, Catherine et al. “Caregiver Burden in Alzheimer's Disease: Differential Associations in Adult-Child and Spousal Caregivers in the GERAS Observational Study.” Dementia and geriatric cognitive disorders extra vol. 4,1 51-64. 19 Feb. 2014, doi:10.1159/000358234

[20] Cummings, J et al. “Lecanemab: Appropriate Use Recommendations.” The journal of prevention of Alzheimer's disease vol. 10,3 (2023): 362-377. doi:10.14283/jpad.2023.30

[21] Ryan, Natalie S et al. “Spontaneous ARIA (amyloid-related imaging abnormalities) and cerebral amyloid angiopathy related inflammation in presenilin 1-associated familial Alzheimer's disease.” Journal of Alzheimer's disease : JAD vol. 44,4 (2015): 1069-74. doi:10.3233/JAD-142325

[22] Harald Hampel, Aya Elhage, Min Cho, Liana G Apostolova, James A R Nicoll, Alireza Atri, Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics, Brain, Volume 146, Issue 11, November 2023, Pages 4414–4424, https://doi.org/10.1093/brain/awad188

[23] Qiao, Yue et al. “Safety and efficacy of lecanemab for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials.” Frontiers in aging neuroscience vol. 15 1169499. 5 May. 2023, doi:10.3389/fnagi.2023.1169499

[24] Johns Hopkins Medicine. "Stages of Alzheimer's Disease." Johns Hopkins Medicine, www.hopkinsmedicine.org/health/conditions-and-diseases/alzheimers-disease/stages-of-alzheimer-disease

[25] Jagust, William. “Is amyloid-β harmful to the brain? Insights from human imaging studies.” Brain : a journal of neurology vol. 139,Pt 1 (2016): 23-30. doi:10.1093/brain/awv326

[26] Marin, Anna, and Andrew E Budson. “Recent advances in understanding Alzheimer's Disease: diagnosis and management strategies.” Faculty reviews vol. 12 24. 10 Oct. 2023, doi:10.12703/r/12-24

[27] Eisai Co., Ltd. "Lecanemab Confirmatory Phase 3 Clarity AD Study Met Primary Endpoint, Showing Highly Statistically Significant Reduction of Clinical Decline in Large Global Clinical Study of 1,795 Participants with Early Alzheimer’s Disease." Eisai Co., Ltd., 28 Sep. 2022, www.eisai.com/news/2022/news202271.html.

[28] Jönsson, Linus et al. “The affordability of lecanemab, an amyloid-targeting therapy for Alzheimer's disease: an EADC-EC viewpoint.” The Lancet regional health. Europe vol. 29 100657. 22 May. 2023, doi:10.1016/j.lanepe.2023.100657

[29] Skaria, Anita Pothen. “The economic and societal burden of Alzheimer disease: managed care considerations.” The American journal of managed care vol. 28,10 Suppl (2022): S188-S196. doi:10.37765/ajmc.2022.89236

[30] "CBS News. 'The real costs of the new Alzheimer's drug, Leqembi — and why taxpayers will foot much of the bill.' CBS News, CBS Interactive, 1 Aug 2023, www.cbsnews.com/news/alzheimers-drug-leqembi-cost-patients-taxpayers.

[31] Ciccone, Isabella, MPH. "Medicare Expands Coverage for Fully Approved Alzheimer Agent Lecanemab." NeurologyLive, 8 July 2023, www.neurologylive.com/view/medicare-expands-coverage-fully-approved-alzheimer-agent-lecanemab

[32] Porsteinsson, A P et al. “Diagnosis of Early Alzheimer's Disease: Clinical Practice in 2021.” The journal of prevention of Alzheimer's disease vol. 8,3 (2021): 371-386. doi:10.14283/jpad.2021.23