By Asmita Anand
Published 11:20 EST, Sun September 5, 2021
Introduction
One of the most common types of dementia in the UK, Alzheimer’s disease (AD) is a physical disease that affects the brain.[1] It is estimated that in 2040 there will be over 1.5 million people with dementia in the UK at the current rate of prevalence.[2] Despite the alarmingly high figures, research is being undertaken to tackle this with 126 different agents currently being assessed to treat Alzheimer’s.[3] Recently, the FDA approved a new drug, aducanumab, for clinical use in Alzheimer’s patients after reviewing evidence on its effectiveness in slowing the progression of symptoms in people with early-stage AD.
What we know:
The effect of Alzheimer’s on the brain
In order to understand how aducanumab treats Alzheimer’s, we must understand the effect AD has on the brain. AD is a neurodegenerative disease. During Alzheimer’s, vital communication between neurons is disrupted as many neurons stop functioning, which results in cell death and leads to shrinking of the brain. This process is known as cerebral atrophy. AD disrupts important processes in neural networks such as communication, metabolism, and repair.[4] As these neurons die, a person suffering from AD will begin to lose the ability to think, remember, make decisions and function independently. This is due to pathological changes and damage to multiple brain structures such the cerebrum, cortex and hippocampus.
The exact cause of AD is still unknown. Many scientists believe that two proteins called ‘beta-amyloid’ and ‘tau’ play a huge role in the toxic changes that occur in the brain. Both of these proteins form the buildup of two abnormal pathologies. The first pathologies are plaques (composed of beta-amyloid) which build up slowly in the neurons and are found scattered between nerve cells. The second pathologies are neurofibrillary tangles formed inside cells which result from the accumulation of abnormal tau. But it is important to note that these are not the only factors which contribute to AD. Furthermore, it is due to the lack of universal acceptance of the amyloid hypothesis that aducanumab has been so heavily criticised, which is explored in further detail below. [5] [6]
What are the current treatment options for AD?
At the moment, treatment for AD revolves around helping patients maintain mental function, slow down progression of symptoms, and manage and ease behavioural symptoms. There are several pharmaceuticals available which can help manage symptoms of Alzheimer’s. Acetylcholinesterase inhibitors are the main drugs used to treat AD in the UK. These include donepezil, galantamine, and rivastigmine. These work by preventing the enzyme acetylcholinesterase from breaking down acetylcholine, a critical neurotransmitter. Levels of acetylcholine are very low in patients with AD due to nerve cell death. By preventing breakdown of this vital chemical, acetylcholine levels will increase, leading to reduction in some symptoms of AD. [7]
The last approved drug was memantine in 2004, which is an oral medication. Unlike the cholinesterase inhibitors which are considered ‘symptomatic’ treatment, memantine is considered a ‘neuroprotective’ drug as it may slow the underlying progression of AD. In AD, too much glutamate leaks out of damaged brain cells, and these high concentrations can result in over-excitation of nerve cells, which leads to cell death.[8] [9] Memantine protects the nerve cells by dampening the excitatory effect of the neurotransmitter glutamate. [10]
What is aducanumab (aduhelm)?
It is an antibody infusion targeting amyloid beta protein (Aß), a defining feature of the biology of AD.[11] Current drugs aim at suppressing cognitive symptoms whereas aducanumab is aiming to tackle the underlying cause of AD, which is to both stop and cure it. Aducanumab is aiming to do this by targeting amyloid, clumps researchers believe are responsible for brain cell death.
The antibody will preferentially bind to aggregated amyloid-beta. This will reduce the presence of amyloid plaques in hopes to slow AD progression.[12] These plaques are also responsible for the inability to perform simple tasks and memory loss.
Back in March 2015, an early-stage clinical trial provided evidence that aducanumab drastically reduced beta-amyloid plaques in the brain. However there were some flaws within this trial such as small testing groups but also the assumption that beta-amyloid oligomers decreased. The latest updates have found that the intermediate deposits, ‘beta-amyloid oligomers’ may be the real culprit and not the end state ‘beta-amyloid plaques’.[13] [14] Four years later and Biogen announced that the development of aducanumab will be discontinued. That is until a couple months later the announcement that the FDA would now be considering it for marketing approval.
The Problems:
The Controversy
The FDA granting accelerated approval is under much speculation. As mentioned earlier, the amyloid hypothesis has influenced a large proportion of Alzheimer’s disease research. The amyloid hypothesis is still doubted by many professionals with its more recent ‘failed’ drug trials adding further doubt.[15] The FDA’s ignorance towards data from the trial which showed no slowing in disease progression is alarming considering the “FDA’s own advisory committee last November voted 8 to 1 against approving the drug, citing “lack of strong evidence that the drug works.”[16] In fact, a member of the of the FDA’s expert panel for nervous system therapies has even gone as far to resign over the FDA ruling, STAT reported.[17]
Even if we were to ignore the lack of data proving any clinical benefits of aducanumab on declining disease progression, the question of whether there is a connection between plaque reduction and cognitive improvement still remains uncertain. Some believe beta-amyloid may not be the underlying cause of the disease at all and hence aducanumab may not be the answer.
Furthermore, we need to be realistic. Professor John Hardy of neuroscience at University College London, said: “We have to be clear that, at best, this is a drug with marginal benefit which will help only very carefully selected patients.” It is likely that aducanumab will be better for those with mild AD and cognitive impairment, as opposed to those with advanced AD.
It’s Future and the Challenges that lie ahead
The potential side effects are another reason to approach aducanumab treatment with caution. Patients undergoing aducanumab treatment will need continual monitoring due to its main side effect, amyloid-related imaging abnormalities (ARIA). ARIA-E refers to cerebral edema or brain swelling, whereas ARIA-H refers to cerebral microhemorrhages or micro bleeds in the brain.
While many have heavily criticised the approval, others are praising it with caution under the acknowledgement that it is far from a cure. The accelerated approval of aducanumab (as opposed to standard approval) is paving a new path for other treatments of neurodegenerative diseases. The ‘accelerated approval’ pathway is used for treatments that are “reasonably likely” but not certain to help patients. Furthermore, the revival of aducanumab is also bringing more interest towards research for treatments of neurodegenerative diseases. As Mario Carrillo, chief science officer at the nonprofit Alzheimer’s Association, has said: “History has shown us that approvals of the first drug in a new category invigorates [sic] the field”.
In order for us to ensure aducanumab could truly be the way forward for AD treatment, companies marketing the drug, Biogen and Eisai, should verify its clinical benefits with further study. While the amyloid hypothesis may be doubtful, there is no reason to give up in this direction of treatment yet.
Conclusion
Uncertainty still remains over aducanumab’s future impact; it is yet to be available in the UK and Europe. Nevertheless aducanumab is providing a spark of hope for our endless search for treatments of AD, as it is the first treatment in a very long time. With dementia research having been chronically underfunded in the UK, the need for new life-changing treatments is only increasing.
As it stands currently, aducanumab is not exactly a cure for Alzheimer’s and there are still many more obstacles we will have to overcome. However, it undoubtedly is a remarkable moment and marks a great milestone in dementia research.
Asmita Anand, Youth Medical Journal 2021
References
[1]Jackie, et al. “What Is the Difference between Dementia and Alzheimer’s Disease?” Alzheimer’s Society, 17 July 2018, www.alzheimers.org.uk/blog/what-difference-between-dementia-and-alzheimers-disease.
[2]“Alzheimer’s Society’s View on Demography.” Alzheimer’s Society, 2020, www.alzheimers.org.uk/about-us/policy-and-influencing/what-we-think/demography.
[3]Cummings, Jeffrey, et al. “Alzheimer’s Disease Drug Development Pipeline: 2021.” Alzheimer’s & Dementia: Translational Research & Clinical Interventions, vol. 7, no. 1, 2021. Crossref, doi:10.1002/trc2.12179.
[4]“What Happens to the Brain in Alzheimer’s Disease?” National Institute on Aging, 2017, www.nia.nih.gov/health/what-happens-brain-alzheimers-disease.
[5]“How Alzheimer’s Changes the Brain.” YouTube, uploaded by National Institute On Aging, 23 Aug. 2017, www.youtube.com/watch?v=0GXv3mHs9AU.
[6]Leonard, Wendy Mph. “Causes of Alzheimer’s Disease.” Healthline, 2 Sept. 2017, www.healthline.com/health/alzheimers-disease-causes.
[7]“How Do Drugs for Alzheimer’s Disease Work?” Alzheimer’s Society, www.alzheimers.org.uk/about-dementia/treatments/drugs/how-do-drugs-alzheimers-disease-work. Accessed 2 July 2021.
[8]“Alzheimers Drug Treatments | Royal College of Psychiatrists.” RC PSYCH ROYAL COLLEGE OF PSYCHIATRISTS, 2015, www.rcpsych.ac.uk/mental-health/treatments-and-wellbeing/alzheimers-drug-treatments.
[9]Liou, Stephanie. “About Glutamate Toxicity – HOPES Huntington’s Disease Information.” HOPES Huntington’s Disease Information, 18 Nov. 2014, hopes.stanford.edu/about-glutamate-toxicity.
[10]Kernisan, Leslie Mph. “4 Medications FDA-Approved to Treat Alzheimer’s & Other Dementias: How They Work & FAQs.” Better Health While Aging, 19 June 2021, betterhealthwhileaging.net/faqs-medications-for-alzheimers-dementia.
[11]Jack, Clifford R., et al. “NIA-AA Research Framework: Toward a Biological Definition of Alzheimer’s Disease.” Alzheimer’s & Dementia, vol. 14, no. 4, 2018, pp. 535–62. Crossref, doi:10.1016/j.jalz.2018.02.018.
[12]Staff, Bns. “Aduhelm (Aducanumab).” Alzheimer’s News Today, 1 July 2021, alzheimersnewstoday.com/aducanumab.
[13]Yu, Han. “We’ve Got the First Alzheimer’s Drug in Decades. But Is It a Breakthrough?” The Guardian, 2 July 2021, www.theguardian.com/commentisfree/2021/jun/28/alzheimers-drug-aducanumab-approval-dementia.
[14]Sevigny, Jeff, et al. “The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer’s Disease.” Nature, vol. 537, no. 7618, 2016, pp. 50–56. Crossref, doi:10.1038/nature19323.
[15]Sabbagh, Marwan Noel, and Jeffrey Cummings. “Open Peer Commentary to ‘Failure to Demonstrate Efficacy of Aducanumab: An Analysis of the EMERGE and ENGAGE Trials as Reported by Biogen December 2019.’” Alzheimer’s & Dementia, vol. 17, no. 4, 2020, pp. 702–03. Crossref, doi:10.1002/alz.12235.
[16]Doheny, Kathleen. “Controversial New Alzheimer’s Drug: What to Know.” WebMD, 9 June 2021, www.webmd.com/alzheimers/news/20210609/controversial-new-alzheimers-drug-what-to-know.
[17]STAT. “Member of FDA’s Expert Panel Resigns over Alzheimer’s Therapy Approval.” STAT, 9 June 2021, www.statnews.com/2021/06/08/fda-expert-panel-resigns-alzheimers-approval/?utm_campaign=KHN%3A First Edition&utm_medium=email&_hsmi=132618545&_hsenc=p2ANqtz-83Omcd8InGsFZ56X_VCnvMvUv0khIW5KtkCzv_xmhbJZHfTbrddSvG8vTBOry6QTzlKkA4sVxAEFsNru_nBzJj4xYUhw&utm_content=132618545&utm_source=hs_email.
“Amyloid-Related Imaging Abnormalities.” Wikipedia, 2021, en.wikipedia.org/wiki/Amyloid-related_imaging_abnormalities.
Servick, Kelly. “Alzheimer’s Drug Approved despite Doubts about Effectiveness.” Science, 2021. Crossref, doi:10.1126/science.abj8372.
Alexander, G. Caleb, et al. “Evaluation of Aducanumab for Alzheimer Disease.” JAMA, vol. 325, no. 17, 2021, p. 1717. Crossref, doi:10.1001/jama.2021.3854.
Schneider, Lon. “A Resurrection of Aducanumab for Alzheimer’s Disease.” The Lancet Neurology, vol. 19, no. 2, 2020, pp. 111–12. Crossref, doi:10.1016/s1474-4422(19)30480-6.
Youth Medical Journal 