Breaking Barriers: The Evolving Landscape of Alzheimer's Treatments

Welcome to the first in our series of articles on Alzheimer’s!

Throughout this series we aim to share a variety of perspectives, ranging from cutting-edge treatments, health economics, technological interventions, and societal implications to the importance of diversity and shifts in patient-centric communication.

The importance of Alzheimer's research cannot be overstated. This relentless disease profoundly affects the lives of millions of patients as well as the lives of their loved ones and caregivers. Advancements in understanding the complex mechanisms of this disease have the potential to transform millions of lives by developing effective prevention strategies, improving early diagnosis, and offering innovative treatments. Each new discovery brings a glimmer of hope to sufferers and their families, as it edges us closer to the ultimate goal - a world without Alzheimer's disease.

Article1 - Breaking Barriers: The Evolving Landscape of Alzheimer's Treatments

In 1906, Dr. Alois Alzheimer, a German physician, provided the first description of what he called "a peculiar disease" characterised by profound memory loss and microscopic brain changes. This condition, now known as Alzheimer's disease (AD), stands as the most prevalent cause of dementia. In fact, Alzheimer's accounts for a substantial majority, ranging from 60% to 80%, of all dementia cases.¹ Furthermore, approximately two-thirds of those affected by Alzheimer's are women.² Alzheimer's is a degenerative disease, with symptoms manifesting gradually and intensifying over time.

With a near-20-year drought in effective new treatments, the pain and stress for patients and their families continues to rise, emphasising the critical need for continued research and enhanced care for those dealing with this devastating condition.

The escalating healthcare costs and burdens of Alzheimer's disease

Alzheimer's disease (AD) represents one of our most pressing health challenges. As the most common neurodegenerative disease, its impact is staggering. Globally, the incidence of AD and other dementias saw an astounding near 150% increase between 1990 and 2019,³ reflecting the growing burden it places on individuals, families, and healthcare systems. In 2016, AD became the 6th most burdensome disease and, in 2021, became the 7th leading cause of death in the United States.^4,5 Currently affecting 6.1 million people in the United States alone, projections paint a grim picture with an expected rise to 13.8 million cases by 2060.⁶ Additionally, the number of AD patients worldwide is expected to exceed 150 million by 2050.⁷ This underscores the urgent need for continued research, awareness, and support to alleviate the profound burden this disease places on society.

In 2019, the estimated global healthcare cost for AD treatment reached US $1.3 trillion, encompassing a range of direct and indirect expenses.⁸ Direct costs include skilled nursing care, home health care, hospice care, doctor's visits, emergency department visits, hospital admissions, and medications. However, it's essential to recognise that indirect costs, which encompass factors like the decreased quality of life and productivity and the extensive demands of informal caregiving, are likely underestimated and carry significant societal and personal burdens.⁹ Informal caregiving, estimated to constitute approximately 75% of care for AD patients, places substantial financial, physical, and emotional strain on caregivers.⁹ Research has shown that treatments capable of delaying AD-related symptom onset by just five years could lead to a 41% reduction in its prevalence and a 40% decrease in the overall cost of AD care by 2050.¹⁰ This would have a profound impact on all aspects of this disease, including the patient's and caregiver's quality of life and the economic strain that this disease causes.

Complexities of Alzheimer's Disease Research

Before aducanumab in 2021, there had been no new FDA-approved treatments for Alzheimer's disease since 2003. But Alzheimer's disease causes such a burden on society, so why not?

The prolonged search for a cure for Alzheimer's disease is attributed to the formidable complexities of the human brain and the multifaceted nature of the condition itself. Researchers have struggled with a fundamental lack of clarity regarding its complex etiology and pathophysiology, with a myriad of factors like genetics, lifestyle, and environmental influences contributing to its development. Additionally, AD often remains undiagnosed until its later stages when significant neurological damage has already occurred, making it challenging to intervene effectively. Ethical considerations and regulatory hurdles further complicate research, particularly due to the involvement of vulnerable populations. The intricate and costly process of developing potential treatments, coupled with numerous failed clinical trials, has led to frustration within the scientific community as well as patients and their support networks.¹³

Disease modification vs symptomatic relief

Prior to a few recent breakthroughs, all FDA-approved AD treatments did not alter disease progression, only managed the symptoms. Additionally, many patients and caregivers noticed no change in memory when taking these medications. These drugs include acetylcholinesterase inhibitors and an N-methyl-D-aspartate receptor agonist. Recent advancements in AD treatment have shifted focus from symptom relief to disease modification and slowing disease progression.

The earliest histopathological sign of AD is amyloid-beta (Aβ) protein deposition in the neocortex, before spreading deeper into the brain. According to the amyloid hypothesis, production of Aβ in the brain initiates a cascade of events leading to the clinical presentation of AD. The most aggregation-prone isoform of Aβ is Aβ42 which has a tendency to cluster and form oligomers. These oligomers can then form Aβ-fibrils that will eventually form amyloid plaques. Aβ40, which makes up approximately 50% of Aβ found in cells, is another somewhat aggregation-prone isoform. The forming of amyloid oligomers initiates the amyloid cascade and results in local inflammation, oxidation, excitotoxicity (excessive glutamate) and tau hyperphosphorylation. Tau protein facilitates the neuronal transport system by binding to microtubules. However, when tau protein is abnormally hyperphosphorylated, it forms insoluble fibrils and intraneuronic tangles. This accumulation results in brain cell damage and death.^13,16 There is some evidence that the progression of AD can be slowed by the removal of Aβ from the brain.¹⁷

Recent disease-modifying breakthroughs

Aducanumab

Aducanumab is a humanised monoclonal antibody that specifically targets aggregated forms of Aβ. Two identical, 18-month, randomised, double-blind, placebo-controlled, phase 3 studies investigated the efficacy of aducanumab in participants with early Alzheimer’s disease. These studies, EMERGE and ENGAGE, recruited 1638 and 1647 patients, respectively, with mild cognitive impairment or mild dementia due to AD. Although ENGAGE did not meet its primary or secondary endpoints, EMERGE showed that aducanumab reduced the clinical decline of AD.¹⁸ Aducanumab was the first disease-modifying AD therapy approved by the FDA in 2021.¹⁹

Lecanemab

Lecanemab is a humanised IgG1 monoclonal antibody that binds to soluble Aβ protofibrils and subsequently removes amyloid plaques in the brain. The efficacy of lecanemab was assessed in Clarity AD—an 18-month, randomised, double-blind, placebo-controlled, phase 3 study involving 1566 patients with early AD. The results from Clarity AD showed that lecanemab reduced the levels of amyloid in the brain and was associated with moderately less decline in cognition and function than placebo at 18 months. Lecanemab was granted full FDA approval in July 2023.²¹

Donanemab

Donanemab is another IgG1 monoclonal antibody that has recently been shown to slow AD progression in patients with early Alzheimer's disease. Donanemab specifically targets and binds insoluble, modified, N-terminal truncated form of Aβ only present in brain amyloid plaques to assist plaque removal through microglial-mediated phagocytosis. In the TRAILBLAZER-ALZ 2 phase III trial of 1736 participants with early AD, donanemab significantly slowed the progression of AD at 76 weeks when compared with placebo. Donanemab is not yet approved by the FDA for AD treatment.

Cost-effectiveness of new Alzheimer’s drugs

Whilst these advancements in AD treatment are exciting, it’s important to consider the cost-effectiveness of these new drugs. All three of the disease-modifying drugs mentioned above have been determined to not be cost-effective in the current state.

Aducanumab was originally priced at $56,000 USD per year and has since been lowered to $28,200; however, a 2022 analysis on the cost-effectiveness of aducanumab suggests that this price would need to decrease to less than $3,000 per year to become cost-effective. This same study determined that for donanemab to be cost-effective, it would have to be priced at or below $20,000 per year. Yet its expected cost is approximately $25,000 per year. Lecanemab has a drug cost of $26,500 per year. In March 2023, ICER calculated that a health-benefit price benchmark (HBPB) for this drug was $8,900 – $21,500 per year, indicating its current pricing represents a low long-term value for money.

In addition to the direct drug costs, ancillary costs need to be considered. Such costs may include procedural costs associated with intravenous infusion, MRI monitoring for amyloid-related imaging abnormalities (ARIA), and costs associated with managing infusion-related reactions and therapy-related adverse events (such as ARIA).

Future outlook

Recent research in mouse models has unveiled a critical pathway involving myeloid cells and their impact on cognition, which might open up the potential for an mRNA vaccine to treat Alzheimer’s disease. Myeloid cells are blood cells that mature to take on specific roles, one of which is a macrophage. m6A methylation occurs through an enzyme called METTL3. By lowering the amount of METTL3 in mouse models, m6A methylation of the DNMT3A gene in blood-derived myeloid cells was downregulated. This inhibited expression of the DNMT3A protein, which ultimately led to the downregulation of ATAT1. ATAT1 blocks the migration of myeloid cells to the brain, thus, by downregulating ATAT1, myeloid cell migration to the brain is enhanced. This research found that by improving myeloid migration to the brain, Aβ clearance by myeloid-derived macrophages was amplified, and AD symptoms were alleviated.

This innovative approach signifies a promising avenue for future Alzheimer's research and the development of potential mRNA-based vaccines to combat this debilitating condition. However, many more studies will be needed to validate these findings and better understand these mechanisms and how they can be translated for use in humans in the future.

References

1. Alzheimer’s Association. What is Alzheimer’s disease? Accessed October 6, 2023. Available at: https://www.alz.org/alzheimers-dementia/what-is-alzheimers
2. Alzheimer’s Association. Why Does Alzheimer’s Disease Affect More Women Than Men? New Alzheimer’s Association Grant Will Help Researchers Explore That Question. Updated February 11, 2016. Accessed October 6, 2023. Available at: https://www.alz.org/blog/alz/february_2016/why_does_alzheimer_s_disease_affect_more_women_tha
3. Li X, Feng X, Sun X, Hou N, Han F, Liu Y. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2019. Front Aging Neurosci. 2022;14:937486. Published 2022 Oct 10. doi:10.3389/fnagi.2022.937486 
4. 2023 Alzheimer's disease facts and figures. Alzheimers Dement. 2023;19(4):1598-1695. doi:10.1002/alz.13016 
5. US Burden of Disease Collaborators, Mokdad AH, Ballestros K, et al. The State of US Health, 1990-2016: Burden of Diseases, Injuries, and Risk Factors Among US States. JAMA. 2018;319(14):1444-1472. doi:10.1001/jama.2018.0158 
6. Rajan KB, Weuve J, Barnes LL, McAninch EA, Wilson RS, Evans DA. Population estimate of people with clinical Alzheimer's disease and mild cognitive impairment in the United States (2020-2060). Alzheimers Dement. 2021;17(12):1966-1975. doi:10.1002/alz.12362
7. GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022;7(2):e105-e125. doi:10.1016/S2468-2667(21)00249-8 
8. Wimo A, Seeher K, Cataldi R, et al. The worldwide costs of dementia in 2019. Alzheimers Dement. 2023;19(7):2865-2873. doi:10.1002/alz.12901
9. Deb A, Thornton JD, Sambamoorthi U, Innes K. Direct and indirect cost of managing alzheimer's disease and related dementias in the United States. Expert Rev Pharmacoecon Outcomes Res. 2017;17(2):189-202. doi:10.1080/14737167.2017.1313118 
10. Zissimopoulos J, Crimmins E, St Clair P. The Value of Delaying Alzheimer's Disease Onset. Forum Health Econ Policy. 2014;18(1):25-39. doi:10.1515/fhep-2014-0013 
11. Mukhopadhyay S, Banerjee D. A Primer on the Evolution of Aducanumab: The First Antibody Approved for Treatment of Alzheimer's Disease. J Alzheimers Dis. 2021;83(4):1537-1552. doi:10.3233/JAD-215065
12. Alzheimer’s Association. Causes and Risk Factors for Alzheimer's Disease. Accessed October 6, 2023. Available at: https://www.alz.org/alzheimers-dementia/what-is-alzheimers/causes-and-risk-factors#:~:text=Researchers%20believe%20there%20isn%27t,increase%20the%20risk%20of%20Alzheimer%27s
13. Yiannopoulou KG, Anastasiou AI, Zachariou V, Pelidou SH. Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines. 2019;7(4):97. Published 2019 Dec 9. doi:10.3390/biomedicines7040097
14. Stanford Medicine Health Care. Medications for Alzheimer's Disease. Accessed September 24, 2023. https://stanfordhealthcare.org/medical-conditions/brain-and-nerves/alzheimers-disease/treatments/medications.html 
15. Tipton PW. Updates on pharmacological treatment for Alzheimer's disease [published online ahead of print, 2023 Aug 22]. Neurol Neurochir Pol. 2023;10.5603/pjnns.96286. doi:10.5603/pjnns.96286 
16. Alzheimer’s Association. Tau. Updated October 2021. Accessed October 6, 2023. Available at: https://www.alz.org/media/Documents/alzheimers-dementia-tau-ts.pdf
17. Avgerinos KI, Ferrucci L, Kapogiannis D. Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease. Ageing Res Rev. 2021;68:101339. doi:10.1016/j.arr.2021.101339 
18. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease. J Prev Alzheimers Dis. 2022;9(2):197-210. doi:10.14283/jpad.2022.30
19. U.S. Food & Drug Administration. FDA Grants Accelerated Approval for Alzheimer’s Drug. June 7, 2021. Accessed September 24, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug 
20. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948 
21. U.S. Food & Drug Administration. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. July 6, 2023. Accessed September 24, 2023. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval 
22. 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 
23. Ross EL, Weinberg MS, Arnold SE. Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease in the US. JAMA Neurol. 2022;79(5):478-487. doi:10.1001/jamaneurol.2022.0315 
24. Institute for Clinical and Economic Review. ICER Publishes Final Evidence Report on Lecanemab for Alzheimer’s Disease. Accessed September 23, 2023. https://icer.org/news-insights/press-releases/icer-publishes-final-evidence-report-on-lecanemab-for-alzheimers-disease/ 
25. Cummings J, Apostolova L, Rabinovici GD, et al. Lecanemab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2023;10(3):362-377. doi:10.14283/jpad.2023.30 
26. Yin H, Ju Z, Zheng M, et al. Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice. PLoS Biol. 2023;21(3):e3002017. Published 2023 Mar 7. doi:10.1371/journal.pbio.3002017