With the USA’s Food and Drug Administration’s recent approval of Donanemab, Medical News Bulletin tracked down an expert to aid us in separating facts from hype. Are Alzheimers monoclonal antibody drugs safe?
In this review of the evidence, we’ll talk you through how these drugs function, what the data says about their safety and whether they really work. Renowned researcher Professor Sandra Black, MD, cognitive neurologist and Alzheimer’s specialist at Sunnybrook Research Institute, Canada helps us get to the bottom of it. What’s up with monoclonals? Do they work and what’s going on with the side effects?
Twenty-First Century Drugs
Alzheimer’s Disease has long been considered an untreatable form of dementia, but since 2021 a new class of anti-Alzheimer’s drugs have taken centre stage. With encouraging clinical trial results, monoclonal antibodies targeted against amyloid are being hailed by some as a ‘game changer’.
The first three antibody-based drugs to be approved by the FDA to treat dementia were Aducanumab, Lecanemab and Donanemab. These drugs are monoclonal antibodies against amyloid, the problem protein that many believe is the culprit behind cognitive decline.
Aducanumab received a controversial accelerated approval by the FDA in 2021 but has since been discontinued by its maker in favour of its more promising successor, Lecanumab1. This was the first hint that monoclonals might have promised more than they can deliver. The FDA took more time to consider and license Lecanemab’s application in 2023, Donanemab was finally approved by the FDA this week.
Underdelivery is one thing, but scary side effects are another. Phase III clinical trial results show that these antibodies can slow down the cognitive decline of patients, yet can also cause swellings and rupturing of blood vessels in the brain. This is unsurprisingly a concern to doctors and patients, but are these side effects as bad as they sound? Maybe not. As we walk you through the underlying biology of what is currently understood about Alzheimer’s disease and amyloid, we hope you will feel empowered to make informed decisions around your care.
Causes of Cognitive Decline
We started by asking Professor Black, what do these drugs do? ‘The idea is to try to preserve the status quo [of people] and not have them decline.’ Says Black. Monoclonal antibodies, she explains, are designed to remove amyloid plaques from the brain. Amyloid Plaques are the hallmark of Alzheimer’s disease. They form when molecules of the protein, amyloid beta, clump together on the surface of brain cells and become entangled. Researchers hypothesize that patches of these protein clumps called ‘plaques’ are involved in damage to the delicate architecture of the brain.
While all people produce amyloid beta, usually when amyloid tangles form, our neurons use their cellular garbage processing machinery to break them down and ship them off to be digested. In patients with Alzheimer’s disease, the excess amyloid does not get cleared, but builds up to form plaques2. Plaque formation can start 10–20 years before the first symptoms appear. This hints that the plaques themselves don’t cause the cognitive symptoms; rather, scientists believe, they initiate a series of molecular events that eventually lead to the death of brain cells2. Once neurons start to die, patients begin to show cognitive symptoms.
The obvious answer therefore was to ask, what would happen if we could clear the Amyloid plaques from the brain before too much damage occurs? Could finding a way to stop Amyloid from accumulating as clumps and tangles prevent patients from losing their memories?
Mono-what?
Enter Monoclonals. Monoclonal antibody-based therapies take their inspiration from our body’s own immune system. You have probably heard of antibodies before, they are tiny Y – shaped molecules made from protein that stick to things that they recognize as pathogens. It could be a foreign object, for example components of bacteria or viruses, even pollen. Antibodies can be very specific, only binding to an exact match for their target, or they can be pretty loose. Once an antibody binds to its target, depending on the type of antibody it is, it will trigger different responses that result in the suspected pathogen being destroyed, disabled or removed.
In the case of monoclonal antibody-based drugs, these are antibodies designed to bind to very specific targets. The antibodies are grown in a lab and carefully processed so that they can safely be injected. These Alzheimer’s drugs are monoclonal antibodies designed to attach to amyloid to help cells in your brain process the excess amyloid faster and get it removed from the brain. The researchers hope that this will both clear existing plaques, and prevent new ones from forming.
Do The Drugs Work?
In patients with mild symptoms of Alzheimer’s Lecanemab and Donanemab seem to remove a significant number of plaques from brains.3,4Encouragingly, clinical trial data shows that using Lecanemab delayed cognitive decline by 27%3. Donanemab, even more by 35%4. Sandra Black translates what these numbers mean for patients: ‘It bought about five or six months of slowing’. Slowing down the decline of cognitive symptoms by half a year does not sound very impressive, but it can bring a much-needed stay for patients on their path to dementia.
For that reason, only patients in early stages, with a mild form of Alzheimer’s profit from this new treatment approach. ‘Mild impairment means that you do have some memory [problems] and other difficulties, but you’re still functioning on all fronts quite well’ clarifies Sandra Black, MD. As biomarker screening improves, earlier application of the drugs could yield more impressive effects, however, for now this seemingly small improvement indicates researchers could be on the right path.
Are Alzheimers monoclonal antibody drugs safe?
So far for the benefits. What about the risks? During clinical trials with amyloid antibodies, physicians noticed abnormalities in the brain scans of Alzheimer’s patients, most often dark dots. Doctors identified these as small brain bleeds. This soon became a concern Black told us: ‘You can run into some injury in the blood vessels and it can lead to what are called “microbleeds” where you get some red blood cells escaping into the brain and they show up as little dark dots. That means that there’s been some injury to the vessel wall and that in some cases can [actually] lead to a cerebral haemorrhage.’ She added that patients can also develop brain swelling when fluid spills into the brain (edema).
These complications show up in brain scans in about 30–40% of patients treated with amyloid antibodies.5 This is about four times more often than patients who received a placebo. However, in most cases, these complications did not cause symptoms and resolved after a few months. For example, about 2.8% of the patients treated with Lecanemab developed brain swelling with symptoms including headache, problems with vision, and confusion; 0.7% of patients developed major bleedings; only 0.2% of patients treated with placebo developed similarly severe complications.3
Crowded Exits
Researchers believe that these problems occur because suddenly all the amyloid gets transported out of the brain through the blood vessels. Black compares the process of removing amyloid plaques from the brain to a congested exit ‘if you’re crowding the exit of a theatre and everybody’s rushing out at once,’ she says, ‘it sort of overwhelms the exit.’ She goes on to explain that removing the chunky protein clumps through the tiny delicate capillaries of the brain can cause tears or thinning of the vessel walls leading to bleeds.
Importantly, having Alzheimer’s already increases your risk for blood vessel damages. ‘Alzheimer’s disease by itself can be a cause of haemorrhage,’ says Sandra Black, MD, ‘and that has to be kept in mind.’ Indeed, the brains of people diagnosed with Alzheimer’s have more blood vessel problems.6 Brain cells receive their nutrients via the bloodstream. If the blood vessels don’t work well, brain cells become undersupplied and ‘stressed’. They produce more amyloid but because the blood vessels are already damaged, the amyloid cannot be effectively removed through the bloodstream. In a vicious cycle, more and more amyloid accumulates.6
Fragile
Since people using these anti-amyloid therapies are more vulnerable to brain bleeds due to their pre-existing amyloid build up, patients prescribed these drugs need careful monitoring.7 Taking blood thinners or a history of stroke or brain bleedings makes complications during the treatment more likely, as well as having certain genetic risk factors for Alzheimer’s. Carrying the APOE4 gene mutation can increase a person’s risk of developing dementia ten fold. Thor actor Chris Hemsworth recently announced he was taking a break from acting after genetic testing revealed that he was at high risk.
Since removal of amyloid plaques from the brain can cause damage, doctors need to carefully monitor patients with frequent brain scans so that they can spot potential blood vessel injuries before they develop into a serious condition. These scans are expensive and inconvenient – especially for older people with restricted mobility or claustrophobic patients.
Individualised Treatment Plans
Therapy with monoclonal amyloid antibodies removes amyloid plaques from the brain and can delay the disease progression for a few months in patients with mild Alzheimer’s. This delay, however, comes with the risk of brain swelling and bleeding. Donanemab, which has recently been approved, seems to be the most effective medication in postponing memory loss while Lecanemab, which is fully approved, seems to be the safer option. Aducanumab could neither demonstrate better efficacy nor safety than the others and has been discontinued. Although severe complications happen in only a small fraction of patients, people with AP04E genetic risk factors for Alzheimer’s and previous records of cardiovascular diseases are much more prone to complications and are generally not suited for this therapy.
Alzheimer’s is a complex disease that has been challenging scientists and doctors for more than a century. The controversy is not confined to treatment approaches either. Recently some scientists have begun to question the amyloid plaque hypothesis.8 Are we sure that the amyloid deposits are causing Alzheimer’s or are they an incidental sign that something else is wrong? Time will tell.
Hard Questions
No Alzheimer’s journey is the same and current treatments can lead to very different outcomes in patients, too. ‘As an individual, you don’t know what’s going to happen to you personally. The people have to enter these trials or enter these treatments with their eyes open,’ says Sandra Black, MD. In the end, each patient has to decide – ideally with the guidance of a specialized physician – how much risk can they tolerate to preserve their memories for a few more months?
What would you risk to keep what you will never get back?
References:
- Biogen to Realign Resources for Alzheimer’s Disease Franchise | Biogen. Accessed June 13, 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-realign-resources-alzheimers-disease-franchise ↩︎
- Wu T, Lin D, Cheng Y, et al. Amyloid Cascade Hypothesis for the Treatment of
Alzheimer’s Disease: Progress and Challenges. Aging Dis. 2022;13(6):1745–1758.
doi:10.14336/AD.2022.0412 ↩︎ - Dyck CH van, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. J
for Neurol Neurochir und Psychiatr. 2021;22(3):142–143. doi:10.1056/nejmoa2212948 ↩︎ - Eli Lilly. Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in
Phase 3 Study of Early Alzheimer’s Disease. https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional. Published 2023. ↩︎ - Yadollahikhales G, Rojas J. Anti-Amyloid Immunotherapies for Alzheimer’s Disease: A
2023 Clinical Update. Neurotherapeutics. 2023; 20(4): 914-931.
doi.org/10.1007/s13311-023-01405-0 ↩︎ - Leszek J, Mikhaylenko E V., Belousov DM, et al. The Links between Cardiovascular
Diseases and Alzheimer’s Disease. Curr Neuropharmacol. 2020;19(2):152–169.
doi:10.2174/1570159×18666200729093724 ↩︎ - Cummings J, Apostolova L, Rabinovici GD, et al. Lecanemab: Appropriate Use
Recommendations. J Prev Alzheimer’s Dis. 2023;3(10):362–377.
doi:10.14283/jpad.2023.34 ↩︎ - Granzotto A, Sensi SL. Once upon a time, the Amyloid Cascade Hypothesis. Ageing Res
Rev. 2024;93 (November 2023):102161. doi:10.1016/j.arr.2023.102161 ↩︎
