tag:theconversation.com,2011:/fr/topics/aducanumab-68565/articlesAducanumab – The Conversation2023-09-15T12:36:15Ztag:theconversation.com,2011:article/2059142023-09-15T12:36:15Z2023-09-15T12:36:15ZAlzheimer’s disease is partly genetic − studying the genes that delay decline in some may lead to treatments for all<figure><img src="https://images.theconversation.com/files/548111/original/file-20230913-29-y9h0zu.jpg?ixlib=rb-1.1.0&rect=8%2C8%2C5483%2C4108&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Researchers are zeroing in on understanding what goes awry in the brains of people with Alzheimer's disease.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/alzheimers-and-dementia-research-conceptual-image-royalty-free-image/1414387544?phrase=alzheimer%27s+disease&adppopup=true">Tek Image/Science Photo Library via Getty Images</a></span></figcaption></figure><p>Diseases that run in families usually have genetic causes. Some are <a href="https://www.genome.gov/For-Patients-and-Families/Genetic-Disorders">genetic mutations</a> that directly cause the disease if inherited. Others are <a href="https://theconversation.com/explainer-what-is-genetic-risk-25969">risk genes</a> that affect the body in a way that increases the chance someone will develop the disease. In <a href="https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet">Alzheimer’s disease</a>, genetic mutations in any of three specific genes can cause the disease, and other risk genes either increase or decrease the risk of developing Alzheimer’s. </p>
<p>Some genetic mutations or variants interact with other genetic alterations that lead to Alzheimer’s disease. In some cases, gene alterations can interact with Alzheimer’s-causing genetic variants in a way that proves beneficial; they actually suppress the pathological brain changes the other mutations would normally lead to. These protective gene variants can drastically slow or prevent cognitive decline. In <a href="https://doi.org/10.1038/s41591-019-0611-3">two recent</a> <a href="https://doi.org/10.1038/s41591-023-02318-3">case reports</a> on familial Alzheimer’s disease, mutations delayed Alzheimer’s symptoms for decades.</p>
<p>I am a <a href="https://scholar.google.com/citations?user=Jbl0lnsAAAAJ&hl=en">neurologist and neuroscientist</a> who has spent my career studying Alzheimer’s disease and dementia both in the laboratory and in the clinic. Determining how genes affect brain chemistry is vital to understanding how Alzheimer’s disease progresses and devising interventions to prevent or delay cognitive decline.</p>
<h2>The amyloid hypothesis</h2>
<p>In the early 1990s, scientists proposed the <a href="https://doi.org/10.1111/j.1750-3639.1991.tb00667.x">amyloid hypothesis</a> to explain how Alzheimer’s disease develops. The first neuropathological changes detected in the brain of Alzheimer’s disease patients were the formation of <a href="https://doi.org/10.1016/0165-6147(91)90609-v">amyloid plaques</a> – clumps of protein pieces called beta-amyloid. Other changes in the Alzheimer’s brain, such as the accumulation of another type of abnormal protein called neurofibrillary tangles, were thought to develop later in the course of the disease.</p>
<p>Beta-amyloid begins to accumulate in the brain <a href="https://doi.org/10.1038/s41582-018-0116-6">up to 15 years</a> before symptoms emerge. Symptoms correlate with the <a href="https://doi.org/10.1007%2Fs00401-019-02036-6">number of neurofibrillary tangles</a> in the brain – the more tangles, the worse the cognition. Researchers have tried to determine whether preventing or removing amyloid plaques from the brain would be an effective treatment. </p>
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<figcaption><span class="caption">Alzheimer’s disease results from the accumulation of abnormal proteins in the brain.</span></figcaption>
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<p>Imagine the excitement of the scientific community in the 1990s when researchers identified three different genes causing familial Alzheimer’s disease – and all three were involved with beta-amyloid.</p>
<p>The first was the <a href="https://doi.org/10.1038/349704a0">amyloid precursor protein</a> gene. This gene directs cells to produce the amyloid precursor protein, which breaks down into smaller fragments, including the beta-amyloid that forms amyloid plaques in the brain.</p>
<p>The second gene was termed <a href="https://doi.org/10.1038/349704a0">presenilin 1, or PSEN-1</a>, a protein needed to cut the precursor protein into beta-amyloid. </p>
<p>The third gene, <a href="https://doi.org/10.1038/376775a0">presenilin 2, or PSEN-2</a>, is closely related to PSEN-1 but found in a smaller number of families with familial Alzheimer’s disease.</p>
<p>These findings added strength to the amyloid hypothesis explanation of the disease. However, <a href="https://doi.org/10.15252/emmm.201606210">uncertainty and opposition to the amyloid hypothesis</a> have developed over the past several decades. This was in part tied to a recognition that several other processes – neurofibrillary tangles, inflammation and immune system activation – are also involved in the neurodegeneration seen in Alzheimer’s. </p>
<p><a href="http://dx.doi.org/10.2174/1570159X15666170116143743">The hypothesis also</a> <a href="https://mitpress.mit.edu/9780262546010/how-not-to-study-a-disease/">got significant pushback</a> after <a href="https://doi.org/10.14283/jpad.2019.23">many clinical trials</a> attempting to block the effects of amyloid or remove it from the brain <a href="https://www.theatlantic.com/health/archive/2017/02/alzheimers-amyloid-hypothesis/517185/">were unsuccessful</a>. In some cases, treatments had significant side effects. Some researchers have <a href="https://doi.org/10.15252/emmm.201606210">come up with strong defenses</a> of the hypothesis. But until a clinical trial based on the amyloid hypothesis could show definitive results, uncertainty would remain. </p>
<h2>Genetic discoveries with treatment implications</h2>
<p>The vast majority – <a href="https://doi.org/10.1016/j.jalz.2016.01.012">more than 90%</a> – of Alzheimer’s cases occur in late life, with disease prevalence increasing progressively from age 65 and up. Such cases are mostly sporadic, with no clear family history of Alzheimer’s.</p>
<p>However, a relatively small number of families have one of the three known genetic mutations that cause the disease to be passed down. In <a href="http://dx.doi.org/10.1016/j.jalz.2016.01.012">familial Alzheimer’s</a>, 50% of each generation will inherit the mutated gene and develop the disease much earlier, usually from their 30s to early 50s.</p>
<p>In 2019 and 2023, researchers identified changes in at least two other genes that markedly delayed the onset of disease symptoms in people with familial Alzheimer’s disease mutations. These mutated genes were found in a very large family in Colombia whose members tended to develop Alzheimer’s symptoms by their 40s.</p>
<p>A <a href="https://doi.org/10.1038/s41591-019-0611-3">woman in the family</a> carrying a mutated PSEN-1 gene <a href="https://www.sciencenews.org/article/colombia-family-genetic-mutation-alzheimers-dementia-treatment">did not have any cognitive symptoms</a> until she was in her 70s. A genetic analysis showed that she had an additional mutation in a variant of the gene that codes for a <a href="https://doi.org/10.1126/science.aba0964">protein called apolipoprotein E</a>, or ApoE. Researchers believe the mutation, called the <a href="https://www.alz.org/news/2022/unlocking-the-christchurch-variant">Christchurch variant</a> – named after the city in New Zealand where the mutation was first discovered – is responsible for interfering with and slowing down her disease. </p>
<p>Importantly, her brain had a great deal of amyloid plaque but very few neurofibrillary tangles. This suggests that the link between the two was broken and that the suppressed number of neurofibrillary tangles also slowed down cognitive loss.</p>
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<figcaption><span class="caption">Researchers have studied certain families in Colombia with rare genetic variants that slow the progression of Alzheimer’s disease.</span></figcaption>
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<p>In May 2023, researchers reported that <a href="https://doi.org/10.1038/s41591-023-02318-3">two siblings in the same large family</a> also did not develop memory problems until their 60s or late 70s and were found to carry a mutation in a gene that codes for a protein called reelin. Studies in mice suggest that reelin has <a href="https://doi.org/10.1038/ncomms4443">protective effects against amyloid plaque deposition</a> in the brain. In these patients’ brains, as with the patient who had the Christchurch variant, there were extensive amyloid plaques but very few neurofibrillary tangles. This observation confirmed that the tangles are responsible for the cognitive loss and that there are several ways to “disconnect” amyloid and neurofibrillary tangle accumulation.</p>
<p>Finding medicines that might mimic the protective effects of the Christchurch variant or the reelin mutation could help delay Alzheimer’s disease symptoms for all patients. Since the vast majority of nonfamilial Alzheimer’s manifests after age 70 or 75, a 10-year delay in the emergence of first symptoms of Alzheimer’s could have a massive effect in <a href="https://doi.org/10.1016/s1474-4422(14)70136-x">decreasing the prevalence of the disease</a>.</p>
<p>These findings demonstrate that Alzheimer’s can be slowed and will hopefully lead to additional new therapies that can someday not only treat the disease but prevent it as well.</p>
<h2>Starts and stops</h2>
<p>Despite over 20 years of doubts and therapy failures, the past several years have seen positive results from three different treatments – aducanumab, lecanemab and donanemab – that remove amyloid plaques and slow loss of cognitive function to some extent. Although there is still discussion of how much slowing of decline is clinically significant, these successes provide support for the amyloid hypothesis. They also suggest that other strategies will be needed for optimal treatment.</p>
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<figcaption><span class="caption">The FDA approved the Alzheimer’s drug aducanumab (Aduhelm) in June 2021, to much controversy.</span></figcaption>
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<p>The U.S. Food and Drug Administration’s 2021 approval of the first antibody treatment for Alzheimer’s, <a href="https://theconversation.com/the-fdas-big-gamble-on-the-new-alzheimers-drug-162396">aducanumab, sold under the brand name Aduhelm</a>, was controversial. Only one of the two clinical trials testing its safety and effectiveness in people yielded positive results. The FDA approved the drug on the basis of that single study through an <a href="https://theconversation.com/the-fda-approved-a-new-drug-to-treat-alzheimers-but-medicare-wont-always-pay-for-it-a-doctor-explains-what-researchers-know-about-biogens-aduhelm-179177">accelerated approval process</a> in which treatments meeting an unmet clinical need can receive expedited approval.</p>
<p>The second antibody, <a href="https://theconversation.com/what-the-fdas-accelerated-approval-of-a-new-alzheimers-drug-could-mean-for-those-with-the-disease-5-questions-answered-about-lecanemab-197460">lecanemab, sold as Leqembi</a>, was approved in January 2023 via the same accelerated approval pathway. It was then <a href="https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval">fully approved</a> in July 2023.</p>
<p>The third antibody, donanemab, completed a successful <a href="https://doi.org/10.1001/jama.2023.13239">phase three clinical trial</a> and is awaiting more safety data. When that is submitted to the FDA, the agency will consider the drug for approval.</p><img src="https://counter.theconversation.com/content/205914/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Steven T. DeKosky consults for Brainstorm Cell Therapeutics and Novo Nordisk Pharmaceuticals; is the Editor for Dementia for Up-To-Date, a point of care electronic textbook of medicine and is Associate Editor of Neurotherapeutics-The Journal of the American Society for Experimental Therapeutics (ASENT); chairs Drug Monitoring Safety Boards for Biogen, Prevail Pharmaceuticals, and Vaccinex Pharmaceuticals; and chairs Scientific Advisory Boards for Acumen Pharmaceuticals and Cognition Therapeutics.</span></em></p>Despite decades of starts and stops, new treatments and key genetic discoveries are giving researchers great hope for slowing or eventually preventing Alzheimer’s disease.Steven DeKosky, Professor of Neurology and Neuroscience, University of FloridaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1974602023-01-13T13:32:38Z2023-01-13T13:32:38ZWhat the FDA’s accelerated approval of a new Alzheimer’s drug could mean for those with the disease – 5 questions answered about lecanemab<figure><img src="https://images.theconversation.com/files/503896/original/file-20230110-26-3yo7ij.jpg?ixlib=rb-1.1.0&rect=0%2C17%2C5991%2C3970&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Alzheimer's disease is an incapacitating, progressive brain disorder that affects the lives of more than 6.5 million Americans. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/serious-asian-senior-woman-in-90s-looking-out-of-royalty-free-image/1296945064?phrase=Alzheimer%27s%20disease&adppopup=true">PamelaJoeMcFarlane/E+ via Getty Images</a></span></figcaption></figure><p><em>The U.S. Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment">approved the medication lecanemab</a>, sold under the brand name Leqembi, on Jan. 6, 2023, through an “<a href="https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval">accelerated approval pathway</a>” that fast-tracks promising clinical treatments for diseases in which there are no other currently effective options.</em> </p>
<p><em>The Conversation asked <a href="https://scholar.google.com/citations?user=GFDRo1QAAAAJ&hl=en">James E. Galvin</a>, a neurologist from the University of Miami School of Medicine who specializes in the study of Alzheimer’s disease and Lewy body dementia, to explain the drug’s clinical potential to help ease the suffering of the roughly 6.5 million Americans who live with Alzheimer’s.</em> </p>
<h2>How does lecanemab work, biologically speaking?</h2>
<p>Lecanemab is a monoclonal antibody that targets beta-amyloid, a naturally occurring protein that becomes toxic when it clumps together to form the <a href="https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour_part_2#">characteristic plaques that accumulate</a> in the <a href="https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease">brains of people with Alzheimer’s disease</a>. The drug is given through intravenous infusions every two weeks.</p>
<p><a href="https://www.livescience.com/antibodies.html">Antibodies are Y-shaped proteins</a> circulating in the blood that recognize and neutralize substances in the body that they see as foreign, such as bacteria and viruses. A <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/monoclonal-antibody">monoclonal antibody</a> is produced by cloning, or making a copy of, a single white blood cell so that all the offshoot antibodies are derived from the same cell and bind to one specific target. In this case, lecanemab binds only to beta-amyloid proteins. </p>
<p>Lecanemab binds to a particular form of beta-amyloid as it clumps, called a protofibril. Studies suggest this is the <a href="https://doi.org/10.1007/s13311-022-01308-6">species of beta-amyloid</a> that is both <a href="https://doi.org/10.3390/ijms22126355">most likely to aggregate into plaques</a> that disrupt cell functioning and to play a role in the development of Alzheimer’s disease. </p>
<p>Earlier trials of other monoclonal antibodies failed to demonstrate a benefit and had more side effects, possibly because they targeted forms of beta-amyloid either <a href="https://doi.org/10.1007/s13311-022-01308-6">too early or too late in the aggregation process</a>.</p>
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<a href="https://images.theconversation.com/files/504342/original/file-20230112-23-7zgk62.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Alzheimer's disease illustration showing misfolded proteins called plaques that aggregate between nerve cells in people with Alzheimer's." src="https://images.theconversation.com/files/504342/original/file-20230112-23-7zgk62.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/504342/original/file-20230112-23-7zgk62.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=333&fit=crop&dpr=1 600w, https://images.theconversation.com/files/504342/original/file-20230112-23-7zgk62.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=333&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/504342/original/file-20230112-23-7zgk62.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=333&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/504342/original/file-20230112-23-7zgk62.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=419&fit=crop&dpr=1 754w, https://images.theconversation.com/files/504342/original/file-20230112-23-7zgk62.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=419&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/504342/original/file-20230112-23-7zgk62.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=419&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Misfolded beta-amyloid proteins aggegrate into clumps, called plaques, that form in the brains of people with Alzheimer’s.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/amyloid-plaques-in-alzheimers-disease-royalty-free-image/1356994685?phrase=alzheimer%27s%20disease%20plaque&adppopup=true">Artur Plawgo/iStock via Getty Images Plus</a></span>
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<h2>Could lecanemab be a game changer for Alzheimer’s treatment?</h2>
<p>Potentially, yes, for people with early-stage Alzheimer’s disease. Medications such as lecanemab have the potential to interfere with the progression of Alzheimer’s disease <a href="https://www.eisai.com/news/2022/news202271.html">by removing beta-amyloid</a> from the brains of people who are suffering with it. </p>
<p>Two recent publications describe results from two different phases of clinical trials.</p>
<p>One study, published in early January 2023, <a href="https://doi.org/10.1056/NEJMoa2212948">reported the results of a phase 3 clinical trial</a> that included 1,795 participants, half of whom received lecanemab and another half who didn’t. In that trial, treatment with lecanemab not only met all its clinical outcomes and safety requirements, but it also reduced the amounts of beta-amyloid measured in imaging tests and in the blood.</p>
<p>Researchers also saw reductions in the levels of tau – the protein responsible for the <a href="https://www.brightfocus.org/news/amyloid-plaques-and-neurofibrillary-tangles">neurofibrillary tangles</a> that accumulate inside the neurons in patient’s with Alzheimer’s. And they found reduced levels of other proteins that measure brain injury and degeneration. This suggests that lecanemab could potentially address the disease by targeting it through both direct and indirect pathways.</p>
<p>A separate study published in December 2022 <a href="https://doi.org/10.1186%2Fs13195-022-01124-2">reported the results of a phase 2 study</a> with 856 participants. Lecanemab treatment also led to significant reductions in amyloid plaques on brain imaging tests, reductions in blood measurements of amyloid and tau protein and slowing of disease progression. These findings provide independent confirmation of the phase 3 findings and support the potential of lecanemab in the treatment of Alzheimer’s disease. </p>
<h2>What were the results?</h2>
<p>After 18 months of treatment <a href="https://doi.org/10.1056/NEJMoa2212948">in the phase 3 study</a>, lecanemab slowed disease progression by 27% compared with the control group. Compared with those who didn’t receive the treatment, participants treated with lecanemab also showed 26% less decline on cognitive testing and a 36% slower loss of function in everyday activities. The study also found a marked reduction in the amount of beta-amyloid deposits in the brains of those who received the treatment. </p>
<p>These outcomes are the some of the largest effects yet seen in any Alzheimer’s disease clinical trial. While not cures, they provide hope that by significantly slowing physical, cognitive and functional decline while also removing amyloid, the course of disease might be altered in a way to give patients improved quality of life. </p>
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<figcaption><span class="caption">Some evidence suggests that amyloid removal slows progression in Alzheimer’s disease.</span></figcaption>
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<p>It is important to remember that the trial was only carried out over 18 months, so we do not fully know the long-term benefits of lecanemab. Ongoing long-term studies will hopefully bring additional insights. However, some <a href="https://doi.org/10.1007/s40120-022-00350-y">recent simulation models</a> have suggested that lecanemab treatment may provide long-term benefits and improve overall quality of life.</p>
<p>While lecanemab has shown clear benefits, it also comes with some notable potential adverse effects that need to be considered. In this case, the concerns are very <a href="https://doi.org/10.1056/NEJMc2215148">specific to treatment with amyloid monoclonal antibodies</a>. </p>
<p>In the phase 3 clinical trial, of the 1,795 participants, 12.6% taking lecanemab experienced swelling of the brain on MRI scans compared to 1.7% of those who received the placebo. Overall, only 2.8% of participants experienced any symptoms – mostly headaches. </p>
<p>In addition, 17.3% of those who received lecanemab had small hemorrhages, or bleeds, of the brain on MRI scans compared to 9% in the placebo group. While few participants experienced complications, at least three deaths due to brain hemorrhage have been reported in individuals enrolled in an ongoing long-term study. But notably, each of these people appear to have <a href="https://doi.org/10.1056/nejmc2215148">had additional risk factors</a>.</p>
<h2>How is lecanemab different from other treatments?</h2>
<p>The currently available Alzheimer’s treatments – which include donepezil, rivastigmine, galantamine and memantine – primarily treat symptoms. They do not address the underlying disease processes, and they have modest clinical benefits. </p>
<p>One medication that does treat the disease, aducanumab, sold under the <a href="https://www.alz.org/alzheimers-dementia/treatments/aducanumab">brand name Aduhelm</a>, was approved by the FDA in 2021 under the same accelerated process as lecanemab. But it has not become widely used due to <a href="https://www.statnews.com/2022/12/29/biogen-set-unjustifiably-high-price-for-alzheimers-treatment-investigation-finds/?">controversy about its efficacy and pricing</a>. </p>
<p>So lecanemab could offer the first disease-modifying medication with undisputed results for people living with the early stages of Alzheimer’s disease. It is important to note that lecanemab was not studied in and was not approved for individuals with moderate or severe stages of Alzheimer’s disease.</p>
<h2>When could lecanemab reach patients who could benefit?</h2>
<p>Although lecanemab has received approval from the FDA, it will likely be several months before it is available for clinical use. </p>
<p>Eisai and Biogen, the pharmaceutical companies that developed lecanemab, recently published <a href="https://www.biopharma-reporter.com/Article/2023/01/10/Next-steps-for-lecanemab-Eisai-reveals-pricing-US-and-global-rollout-plans">guidelines on their pricing policy and roll-out plans</a> for the drug. However, the Center for Medicare and Medicaid Services has said that for now, therapies targeting beta-amyloid <a href="https://www.cms.gov/newsroom/press-releases/cms-statement-fda-accelerated-approval-lecanemab#:">will not be covered by insurance</a> except for those individuals who are enrolled in clinical trials funded by the National Institutes of Health. And commercial insurance companies generally follow Medicare guidance.</p>
<p>Lecanemab will have an estimated out-of-pocket cost of US$26,500 per year. The drugmaker has already filed a supplemental application for traditional FDA approval. If that approval is granted, it is more likely that Medicare and commercial insurance payers will cover most of the cost of lecanemab, which would make the drug much more widely accessible to those living with Alzheimer’s disease.</p><img src="https://counter.theconversation.com/content/197460/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>James E. Galvin provides consultation for Biogen, Eisai, Eli Lilly, Genentech, and Roche. He receives funding from the National Institutes of Health. </span></em></p>In clinical trials, lecanemab slowed disease progression by 27% and reduced the amount of plaque found in the brains of those with Alzheimer’s disease.James E. Galvin, Professor of Neurology, University of MiamiLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1950952022-12-08T19:23:44Z2022-12-08T19:23:44ZLots of ‘breakthroughs’, still no cure. Do the new dementia drugs bring us any closer?<figure><img src="https://images.theconversation.com/files/499696/original/file-20221208-12-yjuyoq.jpg?ixlib=rb-1.1.0&rect=17%2C0%2C5973%2C3359&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">robina weermeijer/unsplash</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>We often hear about “dementia breakthroughs” in the news – new genes being discovered, new blood tests being developed, new drugs being tested. </p>
<p>However, there remains no effective or accessible cure for dementia. This is of great frustration to people living with dementia, and their carers and loved ones.</p>
<p>Two new “breakthrough” drugs have been in the news. While they may not bring much relief to those living with the disease today, we are learning more about dementia, and getting closer to a treatment.</p>
<h2>A bit about dementia</h2>
<p><a href="https://www.dementia.org.au/about-dementia/what-is-dementia">Dementia</a> is an umbrella term to describe a group of conditions characterised by a loss of brain function. This includes the ability to remember, plan and make decisions. </p>
<p>In Australia, dementia is the <a href="https://www.dementia.org.au/statistics">second leading cause of death</a>. For women it’s the leading cause of death. Older age is the greatest risk factor for dementia. But dementia is not an inevitable or normal consequence of ageing.</p>
<p>Up to 70% of all dementia is attributed to Alzheimer’s disease. Other <a href="https://www.dementia.org.au/information/about-dementia/types-of-dementia">types of dementia</a> include vascular dementia, frontotemporal dementia, and Lewy body disease. Because Alzheimer’s is the most common form of dementia, most “dementia breakthroughs” often refer to “breakthroughs” in Alzheimer’s.</p>
<h2>Searching for treatments</h2>
<p>Alzheimer’s disease takes a long time to develop, up to 30 years or more. For a long time, scientists had only a limited understanding of the disease. To develop the right drugs, it’s crucial to have the right tools to be able to understand how the disease progresses. </p>
<p>Over the past 20 years, breakthroughs in brain imaging, brain fluid analysis and, more recently, <a href="https://www.alzforum.org/news/conference-coverage/alzheimers-blood-tests-have-arrived-road-broad-use-still-stretches">blood tests</a>, have enabled us to measure key Alzheimer’s proteins – amyloid and tau – in living people. This has allowed scientists to understand how these proteins develop over time. </p>
<p>We have also been able to clarify which risk factors – age, sex, genetics, environment, lifestyle – contribute to the development of cognitive decline and Alzheimer’s. This provides important insights into who and what to target. </p>
<p><a href="https://www.sciencedirect.com/science/article/pii/S1552526018300724">Studies</a> now suggest Alzheimer’s begins with the buildup of amyloid in the brain. As amyloid builds up, tau then begins to develop. Researchers think it’s this tau buildup that leads to brain cell death and cognitive decline. Some scientists refer to amyloid as the “trigger”, as once the trigger has been pulled, the “bullet” (tau) is on its way. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/499699/original/file-20221208-15-18qate.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Scan of a brain, like an X-ray" src="https://images.theconversation.com/files/499699/original/file-20221208-15-18qate.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/499699/original/file-20221208-15-18qate.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/499699/original/file-20221208-15-18qate.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/499699/original/file-20221208-15-18qate.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/499699/original/file-20221208-15-18qate.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/499699/original/file-20221208-15-18qate.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/499699/original/file-20221208-15-18qate.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Build-up in the brain of a protein called amyloid is the likely trigger for Alzheimer’s.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>Stopping the buildup of amyloid, or removing it, became a key strategy in attempts to develop drugs for Alzheimer’s.</p>
<h2>Two new drugs</h2>
<p>Two drugs that have received a lot of attention in recent weeks are aducanumab (marketed as Aduhelm) and lecanemab. <a href="https://www.nejm.org/doi/10.1056/NEJMc2111960">Both drugs</a> showed substantial <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2212948">reduction in amyloid</a> in the brain. But whether this reduction in amyloid resulted in a meaningful benefit in memory and thinking is less clear.</p>
<p>In two <a href="https://www.nejm.org/doi/10.1056/NEJMc2111960">aducanumab</a> trials, patients did not show any meaningful benefit. But six months later, the drug maker Biogen released and subsequently published new data reporting participants on the highest dose had <a href="https://link.springer.com/article/10.14283/jpad.2022.30">22% slower cognitive decline</a> compared to participants on a placebo.</p>
<p>The Food and Drug Administration in the United States granted <a href="https://www.nejm.org/doi/10.1056/NEJMc2111960">accelerated approval</a> for aducanumab as it thought the drug would improve or slow Alzheimer’s symptoms.</p>
<p>Recently, drug companies Eisai and Biogen announced the results of a lecanemab <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2212948">trial</a>. Around 1,800 participants with early Alzhemier’s were given the drug or a placebo over 18 months. They found a reduction in brain amyloid and tau levels in those taking the drug when compared to participants taking a placebo. </p>
<p>Importantly, lecanemab resulted in a <a href="https://www.bioarctic.se/sv/wp-content/uploads/sites/4/2022/11/clarity-ctad-presentation.pdf">27% slower decline in memory and thinking ability</a>. This was also accompanied by greater quality of life, as reported by participants and their caregivers.</p>
<p>This translates to roughly a six-month benefit in memory and thinking ability. This is not much. In addition, questions have been raised about whether the drug may be less effective for people with higher risk of developing Alzhemier’s, including those with <a href="https://www.dementia.org.au/information/genetics-of-dementia">certain genes</a>, <a href="https://www.aihw.gov.au/reports/dementia/dementia-in-aus/contents/summary">women</a>, and <a href="https://www.aihw.gov.au/reports/dementia/dementia-in-aus/contents/dementia-in-vulnerable-groups/dementia-among-people-from-culturally-and-linguistically-diverse-backgrounds">culturally and linguistically diverse</a> populations. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/499702/original/file-20221208-14-33blyu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Woman looking at camera." src="https://images.theconversation.com/files/499702/original/file-20221208-14-33blyu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/499702/original/file-20221208-14-33blyu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=397&fit=crop&dpr=1 600w, https://images.theconversation.com/files/499702/original/file-20221208-14-33blyu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=397&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/499702/original/file-20221208-14-33blyu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=397&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/499702/original/file-20221208-14-33blyu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=499&fit=crop&dpr=1 754w, https://images.theconversation.com/files/499702/original/file-20221208-14-33blyu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=499&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/499702/original/file-20221208-14-33blyu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=499&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Women and culturally diverse people are more at-risk of dementia.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>There are also substantial side effects that accompany both drugs. Of most concern are brain swelling and small brain bleeds as detected on brain scans. These were observed in <a href="https://jamanetwork.com/journals/jamaneurology/fullarticle/2786606">21-40% of participants</a>. The risk of these side effects will need to be an important discussion between patients, their families and their doctors. </p>
<p>Another consideration is the cost. The price of lecanemab has not yet been announced, but aducanumab costs <a href="https://investors.biogen.com/news-releases/news-release-details/biogen-announces-reduced-price-aduhelmr-improve-access-patients">US$28,200 (A$42,000)</a> per patient per year. Additional costs for brain scanning will also be required to monitor side effects. This makes it <a href="https://n.neurology.org/content/98/9/e968">inaccessible to most people</a> to purchase privately. </p>
<p>It also has consequences for the availability of the drug to be considered under Australia’s Pharmaceutical Benefits Scheme (PBS). Around 150,000 people with mild Alzhemier’s would currently be eligible for aducanumab if it were available. If all of these people received the drug, <a href="https://insightplus.mja.com.au/2022/6/aducanumab-for-alzheimer-disease-opinions-mixed-cost-crazy/">PBS expenditure would increase by 50%</a>.</p>
<p>Companies that develop drugs must provide evidence of their effectiveness to the government health authorities in each country in which they intend to make it available. The governing body in Australia is the Therapeutic Goods Administration. This process has not yet been completed for either drug in Australia.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/chris-hemsworths-alzheimers-gene-doesnt-guarantee-hell-develop-dementia-heres-what-we-can-all-do-to-reduce-our-risk-195094">Chris Hemsworth's Alzheimer's gene doesn't guarantee he'll develop dementia. Here's what we can all do to reduce our risk</a>
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<h2>So why all the breakthroughs, and still no cure?</h2>
<p>Since Alois Alzheimer first described an “<a href="https://www.alzint.org/about/dementia-facts-figures/types-of-dementia/alzheimers-disease/alois-alzheimer/">unusual disease of the cerebral cortex</a>” in 1906, we have learned a lot about the disease and its progression. </p>
<p>But we still have a long way to go. Because Alzheimer’s symptoms take decades to develop, studying and tracking brain and cognitive changes from early in the disease has been difficult. Beyond amyloid and tau, a range of other biological, genetic, lifestyle, and environmental factors can also contribute to Alzheimer’s disease. </p>
<p>It’s unlikely any single one of these factors alone can fully explain why someone develops the disease. It’s likely the disease manifests when several of these risk factors coalesce. For example, someone with a genetic predisposition may be more likely to develop the disease in the face of poor cardiovascular health.</p>
<p>Disentangling the contribution of these risk factors can be challenging. This is why large numbers of people are often required to participate in research.</p>
<p>Given the prevalence of the disease in the community, every advance is seen as newsworthy. And from a scientific point of view, they are.</p>
<p>However these findings, or “breakthroughs,” have not been enough to offer relief to people living with Alzheimer’s or their families, for whom life gets harder every day. Their hopes are dashed when reported “breakthroughs” still haven’t translated into a cure or an effective treatment.</p>
<p>We now have multiple drugs that show some effect in slowing memory deterioration, but the effects are small. Outcomes of more <a href="https://trailblazer3study.com/about-trailblazer-alz-3/">drug trials</a> will be announced in the <a href="https://a4study.org/">coming years</a>.</p>
<p>While these advances may not come fast enough to help people living with the disease now, they’re an important incursion in the war against this devastating disease. They show we’re getting closer.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/experimental-alzheimers-drug-shows-promise-but-there-are-many-hurdles-still-to-overcome-195383">Experimental Alzheimer's drug shows promise – but there are many hurdles still to overcome</a>
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<p><em>If you are interested in learning how to reduce your dementia risk by changing health behaviours, please join us at the <a href="https://www.betterbrains.org.au/">BetterBrains Trial</a>. We are actively recruiting Australians aged 40-70 with a family history of dementia.</em></p><img src="https://counter.theconversation.com/content/195095/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Yen Ying Lim receives funding from the National Health & Medical Research Council (NHMRC), the Australian Research Council (ARC), and the Alzheimer's Association (USA). </span></em></p><p class="fine-print"><em><span>Emily Rosenich does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Two new dementia drugs are being hailed as breakthroughs. But what might be an incremental breakthrough for researchers, doesn’t mean a cure for patients.Yen Ying Lim, Associate Professor, Monash UniversityEmily Rosenich, Postdoctoral Research Fellow (Neuropsychology), Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1890472022-09-19T17:42:12Z2022-09-19T17:42:12ZAlzheimer’s might not be primarily a brain disease. A new theory suggests it’s an autoimmune condition.<figure><img src="https://images.theconversation.com/files/484477/original/file-20220914-12695-vooyej.jpg?ixlib=rb-1.1.0&rect=410%2C914%2C3385%2C2038&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A new theory of Alzheimer's disease reassesses the role of beta-amyloid in the brain.</span> <span class="attribution"><span class="source">(AP Photo/Evan Vucci)</span></span></figcaption></figure><iframe style="width: 100%; height: 100px; border: none; position: relative; z-index: 1;" allowtransparency="" allow="clipboard-read; clipboard-write" src="https://narrations.ad-auris.com/widget/the-conversation-canada/alzheimer-s-might-not-be-primarily-a-brain-disease--a-new-theory-suggests-it-s-an-autoimmune-condition-" width="100%" height="400"></iframe>
<p>The pursuit of a cure for Alzheimer’s disease is becoming an increasingly competitive and contentious quest with recent years witnessing several important controversies. </p>
<p>In July 2022, <a href="https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease"><em>Science</em> magazine</a> reported that a key <a href="https://doi.org/doi:10.1038/nature04533">2006 research paper, published in the prestigious journal <em>Nature</em></a>, which identified a subtype of brain protein called beta-amyloid as the cause of Alzheimer’s, may have been based on fabricated data. </p>
<p>One year earlier, in June 2021, the <a href="https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information">U.S. Food and Drug Administration had approved aducanumab</a>, an antibody-targeting beta-amyloid, as a treatment for Alzheimer’s, even though the data supporting its use were incomplete and contradictory. Some physicians believe aducanumab never should have been approved, while others maintain it should be given a chance. </p>
<p>With millions of people needing an effective treatment, why are researchers still fumbling in this quest for a cure for what is arguably one of the most important diseases confronting humankind?</p>
<h2>Escaping the beta-amyloid rut</h2>
<p>For years, scientists have been focused on trying to come up with new treatments for Alzheimer’s <a href="https://doi.org/10.1016/j.ijbiomac.2020.11.192">by preventing the formation of brain-damaging clumps of this mysterious protein</a> called beta-amyloid. In fact, we scientists have arguably got ourselves into a bit of an intellectual rut concentrating almost exclusively on this approach, often neglecting or even ignoring other possible explanations. </p>
<figure class="align-right ">
<img alt="Illustration showing red clusters of amyloid plaques in brain tissue" src="https://images.theconversation.com/files/485322/original/file-20220919-18-h2kl9f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/485322/original/file-20220919-18-h2kl9f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/485322/original/file-20220919-18-h2kl9f.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/485322/original/file-20220919-18-h2kl9f.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/485322/original/file-20220919-18-h2kl9f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/485322/original/file-20220919-18-h2kl9f.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/485322/original/file-20220919-18-h2kl9f.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Studying beta-amyloids as abnormal proteins that cause Alzheimer’s disease has not translated into a useful drug or therapy.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>Regrettably, this dedication to studying the abnormal protein clumps has not translated into a useful drug or therapy. The need for a new “out-of-the-clump” way of thinking about Alzheimer’s is emerging as a top priority in brain science. </p>
<p>My laboratory at the Krembil Brain Institute, part of the University Health Network in Toronto, is devising a <a href="https://doi.org/10.1002/trc2.12283">new theory of Alzheimer’s disease</a>. Based on our past 30 years of research, we no longer think of Alzheimer’s as primarily a disease of the brain. Rather, we believe that Alzheimer’s is principally <a href="http://dx.doi.org/10.2174/1567205018666211202141650">a disorder of the immune system within the brain</a>.</p>
<p>The immune system, found in every organ in the body, is a collection of cells and molecules that work in harmony to help repair injuries and protect from foreign invaders. When a person trips and falls, the immune system helps to mend the damaged tissues. When someone experiences a viral or bacterial infection, the immune system helps in the fight against these microbial invaders. </p>
<p>The exact same processes are present in the brain. When there is head trauma, the brain’s immune system kicks into gear to help repair. When bacteria are present in the brain, the immune system is there to fight back.</p>
<h2>Alzheimer’s as autoimmune disease</h2>
<p>We believe that beta-amyloid is not an abnormally produced protein, but rather is a normally occurring molecule that is part of the brain’s immune system. It is supposed to be there. When brain trauma occurs or when bacteria are present in the brain, beta-amyloid is a key contributor to the brain’s comprehensive immune response. And this is where the problem begins. </p>
<p>Because of striking similarities between the fat molecules that make up both the membranes of bacteria and the membranes of brain cells, beta-amyloid cannot tell the difference between invading bacteria and host brain cells, and mistakenly attacks the very brain cells it is supposed to be protecting. </p>
<p>This leads to a chronic, progressive loss of brain cell function, which ultimately culminates in dementia — all because our body’s immune system cannot differentiate between bacteria and brain cells.</p>
<figure class="align-right ">
<img alt="Close-up view of a section of a human brain" src="https://images.theconversation.com/files/484487/original/file-20220914-23-iki2y8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/484487/original/file-20220914-23-iki2y8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=455&fit=crop&dpr=1 600w, https://images.theconversation.com/files/484487/original/file-20220914-23-iki2y8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=455&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/484487/original/file-20220914-23-iki2y8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=455&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/484487/original/file-20220914-23-iki2y8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=572&fit=crop&dpr=1 754w, https://images.theconversation.com/files/484487/original/file-20220914-23-iki2y8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=572&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/484487/original/file-20220914-23-iki2y8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=572&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">A section of a human brain with Alzheimer’s disease displayed at the Museum of Neuroanatomy at the University at Buffalo, in Buffalo, N.Y.</span>
<span class="attribution"><span class="source">(AP Photo/David Duprey)</span></span>
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</figure>
<p>When regarded as a misdirected attack by the brain’s immune system on the very organ it is supposed to be defending, Alzheimer’s disease emerges as an autoimmune disease. There are many types of autoimmune diseases, such as rheumatoid arthritis, in which autoantibodies play a crucial role in the development of the disease, and for which steroid-based therapies can be effective. But these therapies will not work against Alzheimer’s disease. </p>
<p>The brain is a very special and distinctive organ, recognized as <a href="https://www.ncbi.nlm.nih.gov/books/NBK234155/#">the most complex structure in the universe</a>. In our model of Alzheimer’s, beta-amyloid helps to protect and bolster our immune system, but unfortunately, it also plays a central role in the autoimmune process that, we believe, may lead to the development of Alzheimer’s. </p>
<p>Though drugs conventionally used in the treatment of autoimmune diseases may not work against Alzheimer’s, we strongly believe that targeting other immune-regulating pathways in the brain will lead us to new and effective treatment approaches for the disease.</p>
<h2>Other theories of the disease</h2>
<figure class="align-center ">
<img alt="A drawing of a brain inside a yellow light bulb, against a green background." src="https://images.theconversation.com/files/484484/original/file-20220914-398-52lw6u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/484484/original/file-20220914-398-52lw6u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/484484/original/file-20220914-398-52lw6u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/484484/original/file-20220914-398-52lw6u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/484484/original/file-20220914-398-52lw6u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/484484/original/file-20220914-398-52lw6u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/484484/original/file-20220914-398-52lw6u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">It is gratifying to see new thinking about this age-old disease.</span>
<span class="attribution"><span class="source">(Pixabay)</span></span>
</figcaption>
</figure>
<p>In addition to this autoimmune theory of Alzheimer’s, many other new and varied theories are beginning to appear. For example, some scientists believe that <a href="https://doi.org/10.1016/j.mito.2022.05.001">Alzheimer’s is a disease of tiny cellular structures called mitochondria</a> — the energy factories in every brain cell. Mitochondria convert oxygen from the air we breathe and glucose from the food we eat into the energy required for remembering and thinking.</p>
<p>Some maintain that it is the end-result of a <a href="https://doi.org/10.4103/1673-5374.339476">particular brain infection</a>, with <a href="https://doi.org/10.1111/prd.12429">bacteria from the mouth often being suggested as the culprit</a>. Still others suggest that the disease may arise from an <a href="https://doi.org/10.3390/biom12050714">abnormal handling of metals within the brain</a>, possibly zinc, copper or iron.</p>
<p>It is gratifying to see <a href="http://dx.doi.org/10.1136/jnnp-2021-327370">new thinking about this age-old disease</a>. Dementia currently affects more than 50 million people worldwide, with a new diagnosis being made every three seconds. Often, people living with Alzheimer’s disease are unable to recognize their own children or even their spouse of more than 50 years.</p>
<p>Alzheimer’s is a public health crisis in need of innovative ideas and fresh directions. For the well-being of the people and families living with dementia, and for the socioeconomic impact on our already stressed health-care system coping with the ever-escalating costs and demands of dementia, we need a better understanding of Alzheimer’s, its causes, and what we can do to treat it and to help the people and families who are living with it.</p><img src="https://counter.theconversation.com/content/189047/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Donald Weaver receives funding from the Canadian Institutes of Health Research and the Krembil Foundation. </span></em></p>Alzheimer’s may not be primarily a disease of the brain. It may be a disorder of the immune system within the brain. Beta-amyloid may not be an abnormal protein, but part of the brain’s immune system.Donald Weaver, Professor of Chemistry and Director of Krembil Research Institute, University Health Network, University of TorontoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1791772022-04-14T12:14:29Z2022-04-14T12:14:29ZThe FDA approved a new drug to treat Alzheimer’s, but Medicare won’t always pay for it – a doctor explains what researchers know about Biogen’s Aduhelm<figure><img src="https://images.theconversation.com/files/456237/original/file-20220404-17-spt0ki.jpg?ixlib=rb-1.1.0&rect=0%2C10%2C7178%2C4031&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">An illustration of amyloid plaques within the human brain, characteristic features of Alzheimer's. By 2060, approximately 14 million Americans are expected to have the disease.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/nerve-cells-affected-by-alzheimers-disease-royalty-free-illustration/1328334584?adppopup=true">Kateryna Kon/Science Photo Library via Getty Images</a></span></figcaption></figure><p><a href="https://www.statnews.com/2022/04/07/medicare-final-decision-alzheimers-coverage-biogen-aduhelm/?utm_source=STAT+Newsletters&utm_campaign=954f9558f2-MR_COPY_01&utm_medium=email&utm_term=0_8cab1d7961-954f9558f2-153726530">Medicare finalized its decision</a> to restrict its coverage of Aduhelm, Biogen’s new Alzheimer’s disease drug, on April 8, 2022.</p>
<p>The decision means only patients who have enrolled in clinical trials <a href="https://www.commonwealthfund.org/blog/2022/medicares-decision-cover-alzheimers-drug-aduhelm-what-will-it-mean-patients-and-program">will receive Medicare coverage for Aduhelm</a>, which goes by the generic drug name of Aducanumab. </p>
<p>Because of the restrictions, many Alzheimer’s patients may be unable to use the drug. Without Medicare coverage, Aduhelm’s annual cost is US$28,200, or $2,350 a month, a price that’s prohibitively expensive for most Americans. </p>
<p>What’s more, not everyone with mild Alzheimer’s will be able to enroll in a clinical trial due to location or other logistical issues. And some of those in the trial may be randomized to only receive a placebo. </p>
<p>Medicare’s ruling clashes dramatically with the Food and Drug Administration’s <a href="https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug">decision in June 2021</a> to approve Aduhelm for all Alzheimer’s patients without restrictions. </p>
<p>This is a departure for Medicare, which <a href="https://doi.org/10.18553/jmcp.2018.24.12.1230">almost always pays for drugs the FDA approves</a>, at least for authorized uses.</p>
<p><a href="https://khn.org/morning-breakout/biogen-pushes-back-against-medicare-decision-over-alzheimers-drug/">Biogen has criticized Medicare’s decision</a>, saying the added requirements “<a href="https://investors.biogen.com/news-releases/news-release-details/biogens-statement-draft-national-coverage-determination-ncd">would significantly restrict</a> and delay patient access to an FDA-approved therapy for a progressive disease.”</p>
<p>But the <a href="https://www.politico.com/news/2022/04/09/alzheimer-drug-aduhelm-medicare-coverage-00024222">core of the issue</a> surrounding this drug is simple: Does it actually work? </p>
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<figcaption><span class="caption">An explainer on Aduhelm, the new drug to treat Alzheimer’s.</span></figcaption>
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<h2>Mixed trial results</h2>
<p><a href="https://einstein.pure.elsevier.com/en/persons/andrew-r-williams">As a physician and researcher</a> who investigates the efficacy of medicines, I have been watching this story unfold over the past year. As of right now, I am certain of one thing: With 6 million people in the United States suffering from Alzheimer’s, and current treatments only marginally effective, there is a desperate need for medications that can slow the disease. </p>
<p>But the evidence on Aduhelm so far is contradictory. Two <a href="https://clinicaltrials.gov/ct2/show/study/NCT02477800">Phase III</a> <a href="https://clinicaltrials.gov/ct2/show/study/NCT02484547">clinical trials</a> were stopped early after an independent committee, appointed by Biogen, analyzed the data and reported the studies were unlikely to show Aduhelm would demonstrate a benefit. This is not unusual; clinical trials are often stopped when early data suggests a drug will not work.</p>
<p>After that analysis, Biogen announced <a href="https://doi.org/10.1016/S1474-4422(19)30480-6">it did find benefits</a> that were statistically significant in one of the trials. This came after evaluating results for 318 participants whose data was not available in time for the initial committee review. That <a href="https://doi.org/10.1002/alz.12286">new data</a> showed the cognitive function of participants in the high-dose group declined 23% more slowly than those in the placebo group. The low-dose group showed no benefit. </p>
<p>While the effects on cognitive decline may seem ambiguous, Aduhelm indisputably <a href="https://doi.org/10.1038/nature19323">reduces patients’ amyloid plaques</a>. It was on this basis that Biogen sought approval for Aduhelm through FDA’s <a href="https://www.fda.gov/drugs/information-health-care-professionals-drugs/accelerated-approval-program">accelerated approval pathway</a>, where drugs treating a serious illness may receive expedited approval if they are reasonably likely to provide a clinical benefit based on some other marker, such as amyloid plaque burden.</p>
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<figcaption><span class="caption">From the CBS Evening News: The challenge to caregivers.</span></figcaption>
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<h2>Background on Aduhelm</h2>
<p>Aduhelm is a monoclonal antibody treatment delivered as an infusion. The drug targets amyloid, a protein that clumps in the brains of Alzheimer’s patients. </p>
<p>While Aduhelm does reduce amyloid plaques in patients’ brains, so do many other medications that haven’t been shown <a href="https://doi.org/10.1136/bmj.n156">to slow cognitive decline</a>. It may be that reducing amyloid plaques does not necessarily improve cognitive function in Alzheimer’s patients. </p>
<p>At the core of the question is the amyloid hypothesis, which has been a central concept of Alzheimer’s research for decades. Simply put, the hypothesis assumes that accumulation of <a href="https://www.alz.org/documents/national/topicsheet_betaamyloid.pdf">the peptide amyloid-B</a> is the primary cause of Alzheimer’s. Many researchers believe that it initiates <a href="https://doi.org/10.1038/d41586-018-05719-4">a cascade of processes</a> that include inflammation and the <a href="https://doi.org/10.1016/j.bbadis.2004.08.014">formation of neurofibrillary tangles</a>, made up of the protein tau, within brain cells. This is thought to lead to dysfunction of the communication points between brain cells known as synapses, which ultimately leads to cell death.</p>
<p>But amyloid plaques are often found in the brains of individuals who <a href="https://dx.doi.org/10.1097%2FNEN.0b013e31822e8ae9">do not have Alzheimer’s</a>. The reduced cognitive function seen in Alzheimer’s is more closely correlated with the number and location of <a href="https://doi.org/10.1097/NEN.0b013e31825018f7">intracellular tau-tangles</a>. It may be that those with <a href="https://www.statnews.com/2020/02/27/alzheimers-brains-but-no-symptoms/">plaques but no symptoms</a> have an early stage of Alzheimer’s.</p>
<h2>Risks and ripple effects</h2>
<p>While the benefits of Aduhelm remain murky, some risks are clear. The same Phase III trials showed that 41% of patients who received the high dose of Aduhelm – the dose that may have led to cognitive benefits – <a href="https://doi.org/doi:10.1001/jamaneurol.2021.4161">experienced cerebral swelling or hemorrhage</a>. Although the majority of these were minor and asymptomatic, a <a href="https://www.nytimes.com/2021/11/22/health/aduhelm-death-safety.html">75-year-old woman in the trial died</a> after experiencing brain swelling and seizures. The risk was considered high enough for the FDA to require the company <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s003lbl.pdf">to place a warning on Aduhelm’s label</a>, advising physicians to monitor patients and obtain two MRI brain scans during the first year of treatment. </p>
<p>Patients selected for the Phase III studies were excluded if they had any of the many medical complications common for older people. This includes cardiac problems, the use of blood thinners or impaired liver or kidney function. These selected patients, who may be healthier than those in the general public who would receive the medication, underwent not two but seven MRIs for monitoring. MRIs are expensive procedures; they <a href="https://doi.org/10.1001/jamahealthforum.2021.4495">raise the real cost</a> of Aduhelm by about 20%. </p>
<p><a href="https://doi.org/10.1038/d41586-022-00651-0">Other anti-amyloid immunotherapy medications</a> are in the pharmaceutical pipeline. More data may emerge to suggest these drugs delay progression of Alzheimer’s, but so far, the relatively minor cognitive benefits seen <a href="https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease">do not seem to match</a> the robust reduction in amyloid plaques. While it’s indisputable that Aduhelm can consistently and convincingly reduce the level of amyloid plaques in the brain, the cognitive benefit it provides to patients remains in doubt. This discrepancy speaks to the complexities of Alzheimer’s – and the holes that remain to be filled in the understanding of this terrible disease.</p>
<p>[<em>Get the best of The Conversation, every weekend.</em> <a href="https://memberservices.theconversation.com/newsletters/?nl=weekly&source=inline-weeklybest">Sign up for our weekly newsletter</a>.]</p><img src="https://counter.theconversation.com/content/179177/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Williams does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Although Medicare has agreed to pay for Aduhelm, its coverage comes with restrictions.Andrew Williams, Assistant Professor of Emergency Medicine, Albert Einstein College of MedicineLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1648452021-07-28T18:23:04Z2021-07-28T18:23:04ZControversial Alzheimer’s drug highlights concerns about Health Canada approval process<figure><img src="https://images.theconversation.com/files/413414/original/file-20210727-25-z25su3.jpg?ixlib=rb-1.1.0&rect=242%2C44%2C5232%2C3939&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Aducanumab (Aduhelm) was approved in the U.S., but there is no convincing evidence the drug will help Alzheimer's patients.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>There’s a new drug on the block to treat Alzheimer’s disease. On June 7, the United States Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug">approved aducanumab</a> (brand name Aduhelm), made by Biogen, the first new drug for Alzheimer’s in 18 years. Biogen has <a href="https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/submissions-under-review/new-drug-submissions-under-review.html">submitted aducanumab for approval</a> here in Canada. </p>
<p>Alzheimer’s is a devastating disease. I see people suffering from dementia almost every day when I’m working in the emergency department in downtown Toronto, and I’ve watched friends stripped of their lives by this disease. So, a drug that could help to relieve their suffering should be cheered on, as the U.S.-based <a href="https://www.alz.org/alzheimers-dementia/treatments/aducanumab">Alzheimer’s Association</a> and the <a href="https://alzheimer.ca/en/about-dementia/how-can-i-treat-dementia/what-aducanumab">Alzheimer’s Society of Canada</a> have hailed aducanumab. </p>
<p>But aducanumab is not such a drug. There is no convincing evidence that aducanumab will make any difference for Alzheimer’s patients. </p>
<h2>Surrogate endpoint</h2>
<p>Aducanumab was approved on the basis of what’s called a surrogate endpoint, which is a measurement that is supposed to reflect progression of a disease. In this case, the surrogate endpoint was the clearing of amyloid plaque — <a href="https://theconversation.com/rethinking-the-approach-to-fighting-alzheimers-disease-120875">abnormal brain deposits often seen in Alzheimer’s patients</a> — from the brains of those with Alzheimer’s. Aducanumab was successful in doing that, but it’s not the first drug that has been shown to clear plaque. </p>
<p>There have been <a href="http://doi.org/10.1001/jama.2021.3854">more than 25 previous trials</a> of plaque-clearing drugs and none of them showed any benefit for people with Alzheimer’s. <a href="https://doi.org/10.2174/156720511795745348">One study</a> followed elderly individuals with plaque and pathological changes typical of Alzheimer’s and found that they had no more cognitive decline that those with “normal” brains.</p>
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<img alt="Illustration of amyloid plaque" src="https://images.theconversation.com/files/413421/original/file-20210727-14-rdinib.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/413421/original/file-20210727-14-rdinib.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/413421/original/file-20210727-14-rdinib.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/413421/original/file-20210727-14-rdinib.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/413421/original/file-20210727-14-rdinib.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/413421/original/file-20210727-14-rdinib.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/413421/original/file-20210727-14-rdinib.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Aducanumab trials used the clearing of amyloid plaque as a surrogate end point.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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<p>Aducanumab is also <a href="http://doi.org/10.1001/jama.2021.3854">not without risks</a>. In the clinical trials, over one-third of patients taking the drug experienced brain changes seen on scans, including some level of brain swelling, versus less than three per cent of those who got the placebo. Almost one per cent of those with changes had severe symptoms, including confusion, disorientation, gait disturbance, ataxia, visual disturbance, headache, nausea, falls and blurred vision.</p>
<h2>FDA controversy</h2>
<p>When the clinical evidence about the drug was presented to a FDA advisory committee of outside experts, <a href="https://www.npr.org/2021/06/11/1005567149/3-experts-have-resigned-from-an-fda-committee-over-alzheimers-drug-approval">10 out of the 11 members voted against the drug’s approval</a> and the 11th was uncertain. Despite this vote, the FDA went ahead and approved aducanumab, prompting three of the committee members to resign in protest. </p>
<p>Although the drug had only been tested in those with mild symptoms, the FDA said it could be used for patients with any degree of Alzheimer’s. Within a few weeks, the FDA <a href="https://www.nytimes.com/2021/07/08/health/aduhelm-alzheimers-fda.html">walked back that decision</a>. Finally, it <a href="https://www.nytimes.com/2021/06/15/opinion/alzheimers-drug-aducanumab-fda.html">gave Biogen until 2030</a> to conduct a study to show that aducanumab actually works.</p>
<p>There are concerns that paying for aducanumab might threaten the <a href="http://doi.org/10.1001/jamainternmed.2021.4610">financial viability of the Medicare Part B</a>, the plan that pays for prescription drugs for U.S. seniors. The total cost in 2018 for all Medicare Part B drugs was US$35 billion. Biogen is charging US$56,000 annually for aducanumab. There are about 5.8 million people with Alzheimer’s who are eligible for Part B coverage. Prescribing aducanumab to just one million of them would cost Medicare an estimated US$57 billion per year.</p>
<p>The independent Boston-based Institute for Clinical and Economic Review calculated that a <a href="https://icer.org/news-insights/press-releases/icer-issues-statement-on-the-fdas-approval-of-aducanumab-for-alzheimers-disease/">fair annual price</a> based on the drug’s presumed effectiveness would be between US$2,500 and US$8,300. Added to the US$57 billion are costs for intravenous infusion of the drug and the PET and MRI scans to see if the drug is clearing brain plaque and to watch for side-effects.</p>
<h2>Health Canada application</h2>
<p>The possible approval of aducanumab by Health Canada highlights a series of debates and concerns about how we approve new drugs. The <a href="https://www.fraserinstitute.org/studies/timely-access-to-new-pharmaceuticals-in-canada-the-united-states-and-the-european-union">Fraser Institute</a>, a free-market think tank, would like Health Canada to dispense with its own reviews and automatically accept any drug approved by either the FDA or the European Medicines Agency. </p>
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Read more:
<a href="https://theconversation.com/fda-approval-of-controversial-alzheimers-drug-could-delay-discovery-of-more-promising-treatments-162481">FDA approval of controversial Alzheimer's drug could delay discovery of more promising treatments</a>
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<p>Given the contortions that the FDA went through to allow aducanumab on the U.S. market, that might not be such a good idea. The <a href="https://www.ourcommons.ca/DocumentViewer/en/43-2/TRAN/report-2">recent report from the House of Commons Standing Committee on Transport, Infrastructure and Communities</a> on Boeing’s 737 Max also highlights the dangers of abandoning regulatory oversight to other governments, in this case Transport Canada’s reliance on the U.S. Federal Aviation Authority.</p>
<p>The FDA Advisory Committee, composed of outside experts, almost unanimously recommended rejecting Biogen’s application to market aducanumab. <a href="https://doi.org/10.9778/cmajo.20190010">Health Canada also uses expert advisory panels and committees</a>for policy issues and technical advice, but not for opinions about whether to approve a new drug. That means that Health Canada will not be getting any outside expert advice about aducanumab. </p>
<p>After the disappointing results of trials on the drug in 2019, Biogen initially decided to abandon work on aducanumab. Subsequently, there are <a href="https://www.bloomberg.com/news/articles/2021-07-09/acting-fda-head-seeks-probe-into-biogen-alzheimer-s-approval">allegations that FDA officials</a> held almost daily back-channel meetings with Biogen throughout the summer of 2019 to determine if there was a way to reinterpret the data and resuscitate the drug. </p>
<p>The acting head of the FDA is <a href="https://twitter.com/DrWoodcockFDA/status/1413540801934774283">requesting an investigation</a> by the inspector general for the Department of Health and Human Services into whether these meetings were inconsistent with the FDA’s policies and procedures.</p>
<p><a href="https://www.canada.ca/en/health-canada/programs/consultation-draft-guidance-accelerated-review-human-drug-submissions.html">Health Canada also meets with companies</a> before they submit drugs for approval so that sponsors can outline the evidence of effectiveness. If meetings have taken place with Biogen there will not be any public record of what was said in them or even if they occurred.</p>
<p>Finally, regardless of whether Health Canada approves or rejects Biogen’s application, we will never see what sort of debate went on inside the agency about the safety and effectiveness of the drug. Health Canada will eventually <a href="https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/clinical-information-drugs-health-products.html">release virtually all of the data</a> that Biogen submitted, but any internal discussions will remain a secret.</p>
<p>Canadians with Alzheimer’s and the clinicians who treat them deserve a drug that works for patients, <a href="https://www.wsj.com/articles/biogens-alzheimers-drug-is-a-wall-street-winner-controversy-or-not-11623086236">not for Wall Street</a>.</p><img src="https://counter.theconversation.com/content/164845/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>In 2017-2020, Joel Lexchin received payments for being on a panel at the American Diabetes Association, for talks at the Toronto Reference Library, for writing a brief in an action for side effects of a drug for Michael F. Smith, Lawyer and a second brief on the role of promotion in generating prescriptions for Goodmans LLP and from the Canadian Institutes of Health Research for presenting at a workshop on conflict-of-interest in clinical practice guidelines. He is currently a member of research groups that are receiving money from the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council. He is a member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare. He receives royalties from University of Toronto Press and James Lorimer & Co. Ltd. for books he has written. </span></em></p>FDA approval of aducanumab (Aduhelm) was contentious. Its submission to Health Canada for approval highlights concerns about evidence, independence and transparency in Canada’s drug approval process.Joel Lexchin, Professor Emeritus of Health Policy and Management, York University, Emergency Physician at University Health Network, Associate Professor of Family and Community Medicine, University of TorontoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1624812021-06-15T20:13:31Z2021-06-15T20:13:31ZFDA approval of controversial Alzheimer’s drug could delay discovery of more promising treatments<figure><img src="https://images.theconversation.com/files/405773/original/file-20210610-15-193m5uv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Alzheimer's disease is characterized by progressive memory loss, spatial disorientation and many other cognitive and behavioural disorders that ultimately lead to a state of total dependence.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>The U.S. <a href="https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug">Food and Drug Administration (FDA) recently approved aducanumab</a>, the first treatment that aims to slow the progression of Alzheimer’s disease. But approval of the drug has provoked mixed reactions from the scientific community.</p>
<p>Alzheimer’s disease is characterized by progressive memory loss, spatial disorientation and many other cognitive and behavioural disorders that ultimately lead to a state of total dependence.</p>
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À lire aussi :
<a href="https://theconversation.com/why-dont-we-have-a-cure-for-alzheimers-disease-156473">Why don't we have a cure for Alzheimer's disease?</a>
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<p>As researchers who study Alzheimer’s biomarkers — objective biological measures used to identify the disease, measure its progression and determine the effectiveness of treatments — we’re very interested in the discovery of new treatments for this disease.</p>
<p>Aducanumab, which will be marketed under the name Aduhelm, was jointly developed by Biogen and Eisai. It is a <a href="https://doi.org/10.1038/s41582-018-0116-6">monoclonal antibody</a> administered by injection that binds to brain aggregates of amyloid and allows our bodies to dispose of them. The treatment is based on the idea that amyloid, a small protein that accumulates in the brains of people with Alzheimer’s disease, is at the origin of a cascade of events that leads to the disease. </p>
<h2>Questionable results</h2>
<p>The FDA approval is based on <a href="https://www.eisai.com/news/2019/news201979.html">two 18-month clinical trials that were conducted with aducanumab</a>. One showed a slowing of the progression of cognitive impairment by about 22 per cent in people who received the high-dose treatment. The other showed no difference between those who were given aducanumab and those given the placebo.</p>
<p>Typically, regulatory authorities require two Phase 3 trials with positive results to approve a drug. Biogen and Eisai terminated both trials after an independent panel of experts concluded that based on preliminary results, aducanumab was unlikely to be effective in slowing the cognitive decline of the disease despite showing some effectiveness in reducing brain amyloid levels.</p>
<p>In addition, aducanumab has been associated with cerebral edema in 40 per cent of those treated. Edema is a fluid mass that produces pressure in the skull and requires medical monitoring or surgery.</p>
<p>After further review of the results from the two clinical trials, Biogen and Eisai announced in <a href="https://www.globenewswire.com/news-release/2019/10/22/1933045/0/en/Biogen-Plans-Regulatory-Filing-for-Aducanumab-in-Alzheimer-s-Disease-Based-on-New-Analysis-of-Larger-Dataset-from-Phase-3-Studies.html">October 2019</a> that aducanumab administered in high doses showed efficacy on cognitive symptoms in patients with early Alzheimer’s. This way of analyzing the results <a href="https://www.doi.org/10.1001/jama.2021.3854">was strongly criticized by the scientific community</a>, including some of the investigators who had participated in the clinical trials.</p>
<h2>Amyloid may have little influence</h2>
<p>The amyloid cascade, the idea behind how aducanumab works, is the subject of <a href="https://doi.org/10.1038/nn.4017">great controversy in the scientific community</a>. This hypothesis has dominated for nearly 30 years and guided the search for treatments that aim to remove amyloid from the brain. Yet every clinical trial using this approach has failed, representing dozens of products and hundreds of billions of dollars in investment.</p>
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<img alt="3D image of neurons with amyloid plaques" src="https://images.theconversation.com/files/405387/original/file-20210609-15107-1m1t9w7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/405387/original/file-20210609-15107-1m1t9w7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/405387/original/file-20210609-15107-1m1t9w7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/405387/original/file-20210609-15107-1m1t9w7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/405387/original/file-20210609-15107-1m1t9w7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/405387/original/file-20210609-15107-1m1t9w7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/405387/original/file-20210609-15107-1m1t9w7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Neurons with amyloid plaques.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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</figure>
<p>More and more, we are realizing that the problems with Alzheimer’s may not involve amyloid either directly or solely. For example, a person who is genetically predisposed to accumulate amyloid may develop Alzheimer’s earlier, but may not progress more rapidly than a person who is not predisposed. This means that amyloid may have little influence on disease progression. </p>
<p>Even advocates of the amyloid hypothesis have become more <a href="https://doi.org/10.1111/jnc.13632">measured about its possible influence</a>, proposing that it may only have an indirect impact on brain dysfunction in Alzheimer’s disease. This would occur through a process of brain inflammation, which is one of the possible causes of neuronal death in this disease.</p>
<p>In short, while the amyloid hypothesis has faltered, the approval of aducanumab, which is based primarily on this theory, suggests that the theory <a href="https://doi.org/10.1038/d41586-021-01546-2">may once again dominate research, and could reduce the chances of finding more promising treatments</a>. For example, tau protein, which also accumulates in the brains of Alzheimer’s patients — <a href="https://doi.org/10.1097/NEN.0b013e318232a379">long before the amyloid protein does</a> — has been shown to be closely associated with the cognitive impairment resulting from the disease.</p>
<h2>A risky precedent</h2>
<p>So how can one explain the FDA’s decision, which runs contrary to the recommendation of its own expert panel and is based on evidence that shows that amyloid only makes a small contribution to the progression of the disease?</p>
<p>Aducanumab reduced the amount of amyloid accumulated in the brain by nearly <a href="https://doi.org/10.1038/nature19323">two-thirds</a> in treated individuals. While this is a dramatic result, their symptoms persisted, meaning that amyloid is not a good biomarker of the disease.</p>
<p>The discovery and validation of reliable biomarkers to detect diseases and assess the efficacy of treatments only comes about after a <a href="https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development">long and rigorous process</a>. The use of amyloid has never really gone through this process, yet the <a href="https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease">FDA approved a treatment</a> based on this. Bypassing this process sets a risky precedent.</p>
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À lire aussi :
<a href="https://theconversation.com/why-dont-we-have-a-cure-for-alzheimers-disease-156473">Why don't we have a cure for Alzheimer's disease?</a>
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<p>No curative treatment targeting Alzheimer’s symptoms has emerged since the first treatments came to market in 1997. Aducanumab is the first approved treatment aimed at slowing the progression of the disease. The surprise and excitement generated by the first success in a journey that has included hundreds of failed clinical trials may explain why the FDA granted the drug conditional approval.</p>
<p>The approval also satisfies the financial interests of Biogen, Eisai and its investors. The most modest estimates put annual revenues from the sale of aducanumab <a href="https://icer.org/news-insights/press-releases/icer-issues-statement-on-the-fdas-approval-of-aducanumab-for-alzheimers-disease/">at more than US$50 billion</a>. Expectation of new revenue for Eisai and Biogen pushed the stock values of these companies up by 75 per cent and 40 per cent respectively the day the announcement was made.</p>
<p>New evidence collected after the launch of aducanumab will be critical to the future of the amyloid hypothesis and our understanding of Alzheimer’s disease. With such a complex disease, it is likely that we will need to develop multiple approaches to stop its progression, much like triple therapy for HIV/AIDS. That’s why we must not interrupt research on biomarkers and new therapeutic approaches.</p><img src="https://counter.theconversation.com/content/162481/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marc Andre Bedard has received funding from the Fonds de recherche du Québec en santé, the Canadian Institutes of Health Research and various pharmaceutical companies including Pfizer, Merck, Shire, Purdue and Novartis.</span></em></p><p class="fine-print"><em><span>Étienne Aumont ne travaille pas, ne conseille pas, ne possède pas de parts, ne reçoit pas de fonds d'une organisation qui pourrait tirer profit de cet article, et n'a déclaré aucune autre affiliation que son organisme de recherche.</span></em></p>The new drug is based on the idea that a build-up of amyloid in the brain leads to the disease. But that hypothesis has been under scrutiny lately.Étienne Aumont, Étudiant au doctorat en psychologie, Université du Québec à Montréal (UQAM)Marc-André Bédard, Professor of cognitive pharmacology, Université du Québec à Montréal (UQAM)Licensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1623962021-06-10T12:35:42Z2021-06-10T12:35:42ZThe FDA’s big gamble on the new Alzheimer’s drug<figure><img src="https://images.theconversation.com/files/405493/original/file-20210609-15107-1w8trnk.jpg?ixlib=rb-1.1.0&rect=0%2C8%2C5360%2C3554&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Do the benefits of approving a drug before confirming it works outweigh the potential costs?</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/senior-woman-comforting-man-with-depression-at-home-royalty-free-image/874789476">monkeybusinessimages/iStock via Getty Images Plus</a></span></figcaption></figure><p>The Food and Drug Administration set off a <a href="https://icer.org/news-insights/press-releases/icer-issues-statement-on-the-fdas-approval-of-aducanumab-for-alzheimers-disease/">firestorm of debate</a> when it approved a new drug, aducanumab, for Alzheimer’s disease via an accelerated approval pathway. This decision ignored the recommendation of the FDA’s <a href="https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information">external advisory panel</a> to reject the drug.</p>
<p>The FDA grants accelerated approvals for drugs to treat serious illnesses for which there are no known, or at least very few, treatments. The type of data used to support accelerated approvals is very different from the typical benchmark safety and efficacy data required for approval. As a <a href="https://scholar.google.com/citations?user=lWAD9d8AAAAJ&hl=en">pharmacist and researcher</a>, I have documented several reasons drug research conducted in a <a href="https://doi.org/10.1002/jcph.1569">laboratory environment differs substantially</a> from what is ultimately seen in people. The challenge lies in striking a balance between taking the time to ensure a treatment works and meeting urgent patient need.</p>
<h2>Using a different standard</h2>
<p>The FDA created an <a href="https://www.fda.gov/drugs/information-health-care-professionals-drugs/accelerated-approval-program">accelerated approval pathway</a> for drugs treating serious diseases for which many patients feel a desperate need for more options. This has included treatment for <a href="https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approvals">advanced-stage cancer, multiple sclerosis and HIV</a>, among others.</p>
<p>When considering accelerated approval, the agency examines a drug’s efficacy using what’s called a “<a href="https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development">surrogate endpoint</a>.” While most drug trials measure success based on <a href="https://dx.doi.org/10.1016%2Fj.conctc.2019.100486">clinical endpoints</a> that determine whether a drug helps people feel better or live longer, like reducing heart attacks or strokes, surrogate endpoints measure <a href="https://dx.doi.org/10.1097%2FCOH.0b013e32833ed177">biomarkers</a> that suggest potential clinical benefit. These surrogate endpoints are viable substitutes for hard clinical endpoints because they’re proven to be directly linked to the desired clinical outcomes. For example, the clinical endpoints of reducing heart attacks and strokes could use reduced blood pressure and low-density lipoprotein (LDL) cholesterol as surrogate endpoints.</p>
<p>While many hypotheses on the correct surrogate endpoints to treat certain diseases have panned out, several others have been shown to be off-base or only partially correct. A great example is <a href="https://medlineplus.gov/lab-tests/homocysteine-test/">homocysteine</a>, an amino acid once thought to be a driver of cardiovascular diseases which since has been shown to be a <a href="https://doi.org/10.1186/1475-2891-14-6">marker of disease only</a>. People with elevated levels of homocysteine are more likely to have cardiovascular disease, but lowering levels doesn’t make heart attacks and strokes less likely to occur. All those who rushed the science and purchased dietary supplements to lower their homocysteine were flushing their money down the drain.</p>
<h2>Testing the amyloid beta hypothesis</h2>
<p>Though the effect of aducanumab, the Alzheimer’s drug developed by biotechnology company Biogen, on <a href="https://icer.org/news-insights/press-releases/icer-releases-draft-evidence-report-on-aducanumab-for-alzheimers-disease/">hard clinical endpoints are lackluster</a>, it has been shown to <a href="https://doi.org/10.1038/nature19323">reduce the formation of amyloid beta plaques</a> in patients with early-stage Alzheimer’s. <a href="https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf">Amyloid beta</a> denotes proteins that clump together to form plaques commonly seen in patients with Alzheimer’s. It’s been hypothesized that these plaques drive the signs and symptoms of Alzheimer’s. <a href="https://doi.org/10.1038/22124">Animal models</a> have shown that interfering with amyloid beta plaque formation could lead to improvements in functioning.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/405240/original/file-20210609-17-l494m8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="PET scan showing the brain of a cognitively healthy person and person with Alzheimer's disease." src="https://images.theconversation.com/files/405240/original/file-20210609-17-l494m8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/405240/original/file-20210609-17-l494m8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=582&fit=crop&dpr=1 600w, https://images.theconversation.com/files/405240/original/file-20210609-17-l494m8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=582&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/405240/original/file-20210609-17-l494m8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=582&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/405240/original/file-20210609-17-l494m8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=732&fit=crop&dpr=1 754w, https://images.theconversation.com/files/405240/original/file-20210609-17-l494m8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=732&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/405240/original/file-20210609-17-l494m8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=732&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Amyloid beta plaques are hypothesized to trigger the neurodegenerative processes of Alzheimer’s disease.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:PET_AD.jpg">The Alzheimer's Disease Education and Referral (ADEAR) Center, NIH/Wikimedia Commons</a></span>
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<p>The data linking amyloid beta plaques to hard clinical endpoints is not a slam-dunk. Unlike <a href="https://doi.org/10.1001/jama.300.11.1343">hypertension</a> and elevated <a href="https://doi.org/10.1177/1074248418769040">LDL cholesterol</a>, which has been proved to be linked to cardiovascular events, <a href="https://doi.org/10.1038/d41586-018-05719-4">amyloid beta</a> has not seen such definitive results. </p>
<p><a href="https://doi.org/10.1002/alz.12235">Two large clinical trials</a> assessing aducanumab have been conducted, one that started with a higher dose and one that started with a lower dose that was later increased. Both trials were stopped early, and the lower-dose trial found no benefits. The higher-dose trial found modest benefits in maintaining mental functioning, but the trial did not have enough patients to show that these benefits were due to the drug and not to chance. After the fact, the researchers combined data from patients who received high-dose aducanumab in both trials and found an <a href="https://doi.org/10.1002/alz.12235">improvement in mental functioning</a>. However, many experts running clinical trials bristle at combining trial outcomes like this: These after-the-fact analyses have been shown in some circumstances to <a href="https://doi.org/10.1097/TP.0000000000000581">not pan out in the future</a>.</p>
<p><a href="https://doi.org/10.1038/s41582-018-0116-6">Other initially promising experimental drugs</a> targeting amyloid beta for Alzheimer’s also fell short in reducing hard clinical endpoints in their clinical trials. After one of these drugs, solanezumab, failed to achieve study aims, additional <a href="https://doi.org/10.1002/alz.12235">data analysis</a> post-trial suggested it might be effective in a select population with mild Alzheimer’s. Researchers conducted an additional large clinical trial focusing on that subpopulation, but again <a href="https://doi.org/10.1002/alz.12235">failed to demonstrate significant benefits</a>. No one knows if aducanumab will find significant benefits when the new clinical trial completes or if it will fail as solanezumab did.</p>
<p>If amyloid beta turns out to be simply a marker and not a cause of Alzheimer’s, it will be a costly mistake: Aducanumab is estimated to cost <a href="https://www.sfgate.com/business/article/FDA-approves-much-debated-Alzheimer-s-drug-16230197.php">over US$56,000 a year</a>.</p>
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<figcaption><span class="caption">The role of amyloid beta plaques in Alzheimer’s disease is still debated among scientists.</span></figcaption>
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<h2>Was the FDA’s ruling a mistake?</h2>
<p><a href="https://www.alz.org/alzheimers-dementia/facts-figures">Over 6 million</a> Americans now have Alzheimer’s disease, and deaths from Alzheimer’s have risen over 145% over the past 20 years. Alzheimer’s disease not only robs individuals of their autonomy but also places a huge burden on family members and the U.S. economy: <a href="https://doi.org/10.1002/alz.12328">$355 billion</a> is spent annually on caring for people with Alzheimer’s. Current FDA-approved treatments are only modestly effective at controlling disease symptoms, and none target a possible underlying cause. </p>
<p>The accelerated approval pathway allows patients with early-stage Alzheimer’s to access aducanumab while a larger and more definitive clinical trial is conducted. Biogen says it hopes to have the clinical trial <a href="https://www.sfgate.com/business/article/FDA-approves-much-debated-Alzheimer-s-drug-16230197.php">completed by 2030</a>. If the study <a href="https://www.fda.gov/drugs/information-health-care-professionals-drugs/accelerated-approval-program">does not find reductions</a> in the hard clinical endpoints, the drug will be withdrawn. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/405239/original/file-20210609-23-arsgwo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Ground sign of Biogen headquarters." src="https://images.theconversation.com/files/405239/original/file-20210609-23-arsgwo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/405239/original/file-20210609-23-arsgwo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/405239/original/file-20210609-23-arsgwo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/405239/original/file-20210609-23-arsgwo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/405239/original/file-20210609-23-arsgwo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/405239/original/file-20210609-23-arsgwo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/405239/original/file-20210609-23-arsgwo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Biotechnology company Biogen applied for FDA approval of aducanumab in October 2019, despite results suggesting it did not work.</span>
<span class="attribution"><a class="source" href="https://newsroom.ap.org/detail/Biogen/3dde8d5dd46441498ffb8d4589961e82">AP Photo/Steven Senne</a></span>
</figcaption>
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<p>If aducanumab is <a href="https://www.alz.org/news/2021/alzheimers-association-fda-approval-aducanumab">ultimately found to be effective</a>, many patients with early-stage Alzheimer’s will <a href="https://www.ajmc.com/view/economic-burden-of-alzheimer-disease-and-managed-care-considerations">reap the benefits</a> in reductions in hospitalizations, doctor visits, nursing home costs and societal burden.</p>
<p>If aducanumab is found to be ineffective, however, Medicare, insurers and patients will have spent tens of millions of dollars on a drug that not only did not work but also exposed patients to adverse events, including the <a href="https://icer.org/news-insights/press-releases/icer-releases-draft-evidence-report-on-aducanumab-for-alzheimers-disease/">risk of bleeding in the brain.</a>.</p>
<h2>Should physicians prescribe aducanumab, and should insurers pay for it?</h2>
<p>For patients in the earlier stages of Alzheimer’s disease, there is <a href="https://doi.org/10.1002/alz.12235">reason to try aducanumab</a> based on the current clinical trial data and the lack of alternatives. But in advanced disease, it is <a href="https://doi.org/10.1038/s41582-018-0116-6">unlikely that aducanumab or any drug targeting amyloid beta</a> will provide benefits.</p>
<p>In a cost-effectiveness assessment of aducanumab, the <a href="https://icer.org/news-insights/press-releases/icer-releases-draft-evidence-report-on-aducanumab-for-alzheimers-disease/">Institute for Clinical and Economic Review</a>, an independent organization assessing the value of medical treatments, suggested an annual price range from $8,300 to $23,000. This is a far cry from the <a href="https://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-launch-multiple-initiatives-help-patients">$56,000 a year the company is expecting to charge</a>, and that doesn’t account for the <a href="https://www.nytimes.com/2021/06/07/health/aduhelm-fda-alzheimers-drug.html">thousands of dollars in additional testing</a> required to reduce the risk of brain swelling and bleeding. </p>
<p>The annual cost of the drug will likely greatly exceed the cost savings in other areas like reduced doctor visits and hospitalizations. Until further results are released, such high costs could lead private insurers to not cover or charge higher copays for the drug. Given the average age of those with Alzheimer’s disease, however, most people receiving aducanumab will be eligible for Medicare and will most likely be covered. Whether the drug will actually treat the disease – the biggest issue in question – remains uncertain.</p>
<p>Let us all hope that the FDA’s gamble pays off.</p><img src="https://counter.theconversation.com/content/162396/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>C. Michael White does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The FDA approved Alzheimer’s disease drug aducanumab despite minimal evidence of its efficacy. Whether this decision ultimately hurts or helps patients depends on data researchers don’t yet have.C. Michael White, Distinguished Professor and Head of the Department of Pharmacy Practice, University of ConnecticutLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1142592019-03-28T10:36:52Z2019-03-28T10:36:52ZAlzheimer’s disease: have we got the cause all wrong?<figure><img src="https://images.theconversation.com/files/266140/original/file-20190327-139368-1lqo83a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/260226050?size=medium_jpg">Fer Gregory/Shutterstock</a></span></figcaption></figure><p>Early in the 20th century, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181715/">Alois Alzheimer</a> first described a disorder of progressive memory loss and confusion in a 50-year-old woman. After she died, he examined her brain and saw that it was full of unusual protein clumps, known as plaques. Over a century later, we know that these plaques are full of a protein called beta-amyloid and are a hallmark of the disease that bears Alzheimer’s name. While other features of Alzheimer’s disease have been discovered, the theory that beta-amyloid is the main cause of this incurable disease has dominated.</p>
<p>There are many subtle variations of the “beta-amyloid hypothesis”, but generally the theory goes that beta-amyloid accumulates in the brain, then clumps together. Somewhere in this process, nerve cells in the brain become damaged, which leads to memory loss and other symptoms of Alzheimer’s disease. So the approach to treating this should be rather straightforward: stop the clumping and you will halt the disease.</p>
<p>Unfortunately, decades of research, many millions of dollars of investment and many failed clinical trials later, it appears that this approach is not working. The most recent plaque-busting treatment to produce disappointing results has been aducanumab – an antibody-based therapy designed to stick to and destroy beta-amyloid.</p>
<p>Initial data suggested that the treatment did, indeed, clear beta-amyloid from the brain. But this week, Biogen and Eisai, the drug companies behind aducanumab, <a href="https://www.wsj.com/articles/biogen-shares-drop-28-after-ending-alzheimers-phase-3-trials-11553170765">ended clinical trials</a> involving thousands of patients early, <a href="http://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials">stating</a> that the “trials were unlikely to meet their primary endpoint upon completion”.</p>
<p>This has led many to ask whether the amyloid hypothesis of Alzheimer’s disease should be abandoned. In reality, few neuroscientists still subscribe to the view that it is the beta-amyloid plaques themselves that cause the symptoms of Alzheimer’s disease. </p>
<p>Studies with mice that mimic human Alzheimer’s disease have shown that memory loss occurs before plaques form in the brain. Other studies have suggested that it is the smaller fragments (“oligomers”) of beta-amyloid that are really toxic to nerve cells. And it has even been suggested that the formation of plaques is a way for the brain to round-up all these dangerous oligomers into one place for safety. </p>
<p>It’s very hard to tell without the full information from the aducanumab trial, but maybe the disease had progressed too far in the participants for the treatment to be effective. Perhaps the small beta-amyloid oligomers had already done their damage, setting the disease in motion before the participants were even recruited to the trial.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/266146/original/file-20190327-139352-5p2fea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/266146/original/file-20190327-139352-5p2fea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/266146/original/file-20190327-139352-5p2fea.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/266146/original/file-20190327-139352-5p2fea.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/266146/original/file-20190327-139352-5p2fea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/266146/original/file-20190327-139352-5p2fea.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/266146/original/file-20190327-139352-5p2fea.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Amyloid-beta plaques (yellow) clumping around brain cells (blue).</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/1157052994?size=medium_jpg">Juan Gaertner/Shuterstock</a></span>
</figcaption>
</figure>
<h2>Alzheimer’s disease vs Alzheimer’s dementia</h2>
<p>At a recent Alzheimer’s Research UK Conference, there was near universal agreement that it’s time to separate the concept of Alzheimer’s disease from the menace of dementia. </p>
<p>Alzheimer’s disease is defined as the build up of beta-amyloid plaques and tangles of another protein, tau, combined with some mild memory changes. Dementia is a symptom of this disease. Advances in brain imaging mean that doctors can now spot these indicators of Alzheimer’s disease much earlier (up to 25 years before dementia symptoms set in). An astonishingly under-reported fact is that progression to dementia is not a given. Not all people who show these clinical signs of Alzheimer’s disease will progress to dementia in their lifetimes.</p>
<p>We are only beginning to study the reasons that some people with Alzheimer’s disease avoid Alzheimer’s dementia. Age is the single biggest risk factor for this progression; the younger you are when beta-amyloid starts to build up in the brain, the more likely you are to suffer from dementia. Diet, education and head injuries may also play a role in this process, but to what extent we do not know.</p>
<p>Another major factor we are only just beginning to understand is genetics. Small variations in our genes seem to influence not only whether we will get a build up of beta-amyloid in the brain, but whether that accumulation leads to dementia symptoms. </p>
<p>The process of finding these so-called “risk genes”, however, is slow. Progress has mostly come from “big data” studies that track tiny changes in the two billion odd DNA bases of the human genome across tens of thousands of individuals and try to find patterns between these changes and rates of Alzheimer’s. </p>
<p>There are around 30 areas of the human genome that have been linked to the risk of developing Alzheimer’s dementia, although there are certainly more to be discovered.</p>
<h2>Aducanumab: right treatment, wrong time?</h2>
<p>As with treatments for many other human diseases, it might be that treatments such as aducanumab might only be effective if they are given early enough, before the disease has caused irreversible changes. A better understanding of the environmental and genetic factors behind Alzheimer’s disease combined with ever more sensitive brain imaging techniques will help doctors identify warning signs even earlier, before even minor memory loss occurs. </p>
<p>While screening and diagnosing people – before symptoms have set in – for an as-yet incurable disease, raises many ethical dilemmas, it might present a fresh window of opportunity to retest beta-amyloid drugs, such as aducanumab. Ultimately, we need to focus our research on understanding the early stages of the disease so that we can prevent Alzheimer’s disease before dementia takes hold.</p><img src="https://counter.theconversation.com/content/114259/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Vicky Jones receives funding from The Dowager Countess Eleanor Peel Trust and BK's Heroes.</span></em></p>Protein tangles have been blamed for causing Alzheimer’s – but drugs that target them keep failing.Vicky Jones, Senior Lecturer in Cell Biology, University of Central LancashireLicensed as Creative Commons – attribution, no derivatives.