tag:theconversation.com,2011:/fr/topics/a-beta-64781/articlesA-beta – The Conversation2021-06-10T12:35:42Ztag: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>
<figcaption>
<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>
</figcaption>
</figure>
<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>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/Y9nrvdPUqyA?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The role of amyloid beta plaques in Alzheimer’s disease is still debated among scientists.</span></figcaption>
</figure>
<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>
<figcaption>
<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>
</figure>
<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/1141142019-04-25T10:43:50Z2019-04-25T10:43:50ZNo cure for Alzheimer’s disease in my lifetime<figure><img src="https://images.theconversation.com/files/267411/original/file-20190403-177181-1xjl0a1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">In most cases, scientists are still unsure of what causes Alzheimer's disease.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/colorful-vector-illustration-scientists-researching-brain-1188871114">FGC / Shutterstock.com</a></span></figcaption></figure><p>Biogen recently announced that it was abandoning its late stage drug for <a href="https://theconversation.com/what-causes-alzheimers-disease-what-we-know-dont-know-and-suspect-75847">Alzheimer’s</a>, <a href="https://www.statnews.com/2019/03/21/biogen-eisai-alzheimer-trial-stopped/">aducanumab</a>, causing investors to <a href="https://www.cnbc.com/2019/03/21/biogen-shares-plunge-more-than-25percent-after-ending-trial-for-alzheimers-drug-aducanumab.html">lose billions</a> of dollars. </p>
<p>They should <a href="https://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-alzheimers-statement?r3f_986=https://www.google.com/">not have been surprised</a>. </p>
<p>Not only have there been more than <a href="https://www.scientificamerican.com/article/why-alzheimer-s-drugs-keep-failing/">200 failed trials</a> for Alzheimer’s, it’s been clear for some time that researchers are likely decades away from being able to treat this dreaded disease. Which leads me to a prediction: There will be no effective therapy for Alzheimer’s disease in my lifetime.</p>
<p>Clinically, I am an emergency physician. But my research interests <a href="https://doi.org/10.1016/j.ajem.2016.08.018">include diagnostic biomarkers</a>, which are molecular indicators of disease, and a diagnostic test for Alzheimer’s is something of a holy grail. </p>
<p>Alzheimer’s sits right at the confluence of a number unfortunate circumstances. Stick with me on this – it’s mostly bad news for anyone middle-aged or older, but there’s a reward of sorts at the end. If you understand why there won’t be much headway on Alzheimer’s, you’ll also understand a bit more why modern medicine has been having fewer breakthroughs on major diseases.</p>
<h2>We don’t know what causes this disease</h2>
<p><a href="https://pdfs.semanticscholar.org/a5b7/42b5a09aae2d5ef53e7129174715dd9e1226.pdf">For decades</a> it was widely believed that the cause of Alzheimer’s was the build-up of abnormal proteins called <a href="https://doi.org/10.1038/d41586-018-05719-4">amyloid</a> and <a href="https://www.sciencemag.org/news/2016/05/tau-protein-not-amyloid-may-be-key-driver-alzheimer-s-symptoms">Tau</a>. These theories dominated the field and led some to believe we were <a href="https://www.webmd.com/alzheimers/news/20180725/new-drug-shows-promise-against-alzheimers">on the verge of effective treatments</a> – through preventing or removing these abnormal proteins. But had the theories been correct we would likely have had at least one or two positive clinical trials. </p>
<p>In retrospect, the multi-decade <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797629/">amyloid</a> fixation looks like a <a href="https://www.amazon.com/Dogmatism-Science-Medicine-Dominant-Monopolize/dp/0786463015">mistake</a> that could have been avoided. Although there is a correlation between amyloid and risk of Alzheimer’s, there are elderly people whose brains have <a href="https://news.northwestern.edu/stories/2016/11/elderly-discovered-with-superior-memory-and-alzheimers-pathology/">significant amounts of the protein</a> and yet are <a href="https://www.statnews.com/2016/11/14/alzheimers-brain-amyloid-plaque/">cognitively intact</a>. <a href="https://doi.org/10.1212/01.wnl.0000219668.47116.e6">Versions of this observation</a> date back to at least <a href="https://doi.org/10.1016/0022-510X(68)90154-8">the 1960s</a>. That’s one reason why researchers <a href="https://doi.org/10.1186/s40478-014-0135-5">have questioned the enthusiasm</a> for this one hypothesis. </p>
<p>It was always possible that the classic plaques and tangles first seen by <a href="https://doi.org/10.1093/brain/awv316">Alois Alzheimer</a>, and now known to be made of abnormal proteins, were <a href="https://doi.org/10.1016/j.jalz.2013.11.003">epiphenomena of aging</a> and not the cause of the disease. Epiphenomena are characteristics that are associated with the disease but are not its cause.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/0GXv3mHs9AU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Changes occurring in the brain of people with Alzheimer’s disease.</span></figcaption>
</figure>
<p>But even more convincing that researchers are closer to the beginning than the end in understanding the cause of Alzheimer’s is the long list of alternative theories. This now includes but is not limited to: <a href="https://www.npr.org/sections/health-shots/2018/09/09/645629133/infectious-theory-of-alzheimers-disease-draws-fresh-interest">infection</a>, <a href="https://www.the-scientist.com/features/what-causes-alzheimers-41982">disordered inflammation</a>, abnormal <a href="https://doi.org/10.1177/193229680800200619">diabetes-like</a> metabolism and numerous environmental <a href="https://doi.org/10.2174/1567205012666150204121719">toxins</a>. </p>
<p>And the past few years have seen more evidence for <a href="https://www.medicalnewstoday.com/articles/322223.php">viral</a>, <a href="https://www.newscientist.com/article/2191814-we-may-finally-know-what-causes-alzheimers-and-how-to-stop-it/">bacterial</a> and <a href="https://doi.org/10.3233/JAD-132681">fungal infections</a>. These <a href="https://doi.org/10.1016/S0140-6736(96)10149-5">viral</a> and <a href="http://blogs.discovermagazine.com/d-brief/2019/01/23/dental-infection-may-spur-alzheimers-disease/#.XJ5dG5hKhhE">bacterial</a> hypotheses were portrayed as eureka moments. But this begs the question: How did powerful tools of epidemiology miss associations with things like cold sores and gum disease? </p>
<h2>Not one disease with one cause</h2>
<p>When Occam’s razor – the principle that the simplest solution is often the best – is applied to this laundry list of possible causes, it leads to some profound implications. Either <a href="https://www.sciencedaily.com/releases/2018/12/181204183713.htm">Alzheimer’s is not one disease</a>, or many factors can contribute to triggering or promoting it. Some authorities have been trying to make such arguments <a href="https://doi.org/10.1002/ana.21736">for some time</a>.</p>
<p>Either of these would be bad news, since we would need to develop multiple effective treatments, possibly in combination. </p>
<p>Unfortunately, our biomedical system is designed for the development and testing of one drug at at time. Combinations of drugs dramatically increase the number of clinical trials needed to test for efficacy and toxicity. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/267412/original/file-20190403-177190-19zc6dk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/267412/original/file-20190403-177190-19zc6dk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=375&fit=crop&dpr=1 600w, https://images.theconversation.com/files/267412/original/file-20190403-177190-19zc6dk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=375&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/267412/original/file-20190403-177190-19zc6dk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=375&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/267412/original/file-20190403-177190-19zc6dk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=471&fit=crop&dpr=1 754w, https://images.theconversation.com/files/267412/original/file-20190403-177190-19zc6dk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=471&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/267412/original/file-20190403-177190-19zc6dk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=471&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">These are just some of the risk factors for Alzheimer’s disease.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/risk-factors-disease-icon-design-infographic-1014218830">iLoveCoffeeDesign / Shutterstock.com</a></span>
</figcaption>
</figure>
<h2>We’ve ignored the biology of aging</h2>
<p>For 50 years after Alzheimer described the <a href="https://doi.org/10.1093/brain/awv316">first patient</a>, the disease was considered relatively rare. Called pre-senile dementia, it struck relatively early and sometimes ran in families. The much more common dementia of old age - senile dementia - was considered part of <a href="https://doi.org/10.1002/ana.21915">aging</a>. </p>
<p>But here’s the thing – regardless of type, Alzheimer’s has a powerful age-related association. This is true even for patients with early-onset inherited form of Alzheimer’s. Give someone the worst possible genome for Alzheimer’s – including the dreaded <a href="https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet">APOE e4 gene</a> that may be associated with a 10-fold increase in risk - and that person still needs to age a bit before developing the disease.</p>
<p>Combine the long list of risk factors with the powerful age association and Alzheimer’s comes into focus. Neurons may be the high-wire act of cell types, and the senescence of aging inexorably wears on them. Any one of many cellular insults may accelerate neurons toward earlier cell death. The worst of these may be a particularly bad gene you inherited from your parents, but all are additive to a greater or lesser degree. </p>
<p>If correct, this conception of the disease means we’re even further away from an effective treatment.</p>
<p>Aging is not disease. It is the normal arc of life and an ineluctable part of being human (“dust unto dust”). As such, the biology of aging <a href="https://www.medpagetoday.com/neurology/alzheimersdisease/75075">didn’t get</a> the attention that was bestowed on organ systems and diseases during the golden years of research funding. </p>
<p>In retrospect, I think this may have been a grave mistake. If you list the risk factors for the major diseases of modern life – heart disease, diabetes, dementia – the most powerful is almost always age. </p>
<p>Bottom line: We also lack an understanding of the basic science of Alzheimer’s most important risk factor.</p>
<h2>We can’t even accurately diagnose this disease</h2>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/267415/original/file-20190403-177190-lu75rw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/267415/original/file-20190403-177190-lu75rw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/267415/original/file-20190403-177190-lu75rw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=908&fit=crop&dpr=1 600w, https://images.theconversation.com/files/267415/original/file-20190403-177190-lu75rw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=908&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/267415/original/file-20190403-177190-lu75rw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=908&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/267415/original/file-20190403-177190-lu75rw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1140&fit=crop&dpr=1 754w, https://images.theconversation.com/files/267415/original/file-20190403-177190-lu75rw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1140&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/267415/original/file-20190403-177190-lu75rw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1140&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Alois Alzheimer’s patient Auguste Deter in 1902. Hers was the first described case of what became known as Alzheimer’s disease.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/1/1d/Auguste_D_aus_Marktbreit.jpg">Wikimedia</a></span>
</figcaption>
</figure>
<p>While it is widely known that it is not possible to diagnose Alzheimer’s accurately during life, a dirty little secret of Alzheimer’s research is that a significant fraction of patients cannot be categorized <a href="https://n.neurology.org/content/38/11/1682.short">even on autopsy</a>. The classic plaques and tangles that Alois Alzheimer saw through his microscope may <a href="https://doi.org/10.1002/ana.410300410">not be accurate</a> biomarkers of this disease.</p>
<p>The single absolute requirement for the development of therapies is an accurate diagnostic. You can’t begin to develop a drug if you can’t accurately identify who has and does not have the disease. Alzheimer’s is the quintessential example of this, as it is very difficult to diagnose. In living patients, diseases like <a href="https://www.nhlbi.nih.gov/health-topics/vascular-dementia">vascular dementia</a> and <a href="https://www.nia.nih.gov/health/what-lewy-body-dementia">Lewy body dementia</a> can be indistinguishable from Alzheimer’s. Some of the newest technologies are actually based on imaging amyloid, which some studies show <a href="https://www.statnews.com/2016/11/14/alzheimers-brain-amyloid-plaque/">may not be a reliable diagnostic test</a>.</p>
<h2>Lead times for new therapies are longer than predicted</h2>
<p>It takes a long time for the Food and Drug Administration to approve a drug. From the moment a possible drug is first conceived, it is often <a href="https://www.medicinenet.com/script/main/art.asp?articlekey=9877">more than 10 years</a> until it is available. </p>
<p>The brain has few if any <a href="https://www.npr.org/sections/health-shots/2018/03/07/591305604/sorry-adults-no-new-neurons-for-your-aging-brains">repair</a> mechanisms. So when we talk about Alzheimer’s treatments, we mean prevention not reversal. </p>
<p>The natural history of Alzheimer’s is such that preventive therapy will need to be started early in the course of the disease. This will add years to the drug development cycle. A decade from discovery to bedside would be good news for an Alzheimer’s drug.</p>
<p>But history teaches us that the delays could be even worse. Shortly after the discovery of genetic engineering in the early 1980s, it was common to tell patients with diseases like sickle cell that a genetic cure was just a <a href="https://www.statnews.com/2018/06/06/drug-development-speed-new-medicines/">few years away</a>. The sickle cell abnormality and its location in the genome had been known for <a href="http://www.bloodjournal.org/content/63/2/249.short?sso-checked=true">some time</a>. The organ system involved is easy to access. Thirty years later we have still not successfully cured diseases like sickle cell, and the hubris of those early predictions are painful memories for older physicians like myself. </p>
<p>The situation with Alzheimer’s looks much worse than sickle cell disease looked back in the 1980s. We don’t know the cause – which is likely multifactorial - and its in a hard to get at organ. And neurological diseases are a particular challenge because the brain is protected behind something called the blood-brain barrier. Even if you have a potentially effective drug, it may not reach its target.</p>
<p>Add all of these considerations together and the long road stretches out ahead. </p>
<p>But no drug for the foreseeable future does not mean there’s nothing to do. There is some indication that healthy lifestyle efforts may <a href="https://theconversation.com/what-causes-alzheimers-disease-what-we-know-dont-know-and-suspect-75847">prevent Alzheimer’s</a>. And even if they don’t, they’re likely effective in preventing <a href="https://www.mayoclinic.org/diseases-conditions/vascular-dementia/symptoms-causes/syc-20378793">vascular dementia</a>, which is <a href="https://www.mayoclinic.org/diseases-conditions/dementia/symptoms-causes/syc-20352013">almost as common</a>.</p><img src="https://counter.theconversation.com/content/114114/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Norman A. Paradis 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>After the failure of multiple drug trials the outlook for an Alzheimer’s drug is bleak. This shouldn’t be a surprise. We don’t know the cause or even how to diagnose the disease.Norman A. Paradis, Professor of Medicine, Dartmouth CollegeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1141352019-03-27T18:25:51Z2019-03-27T18:25:51ZAn unexpected pathway to treating neurodegenerative diseases<figure><img src="https://images.theconversation.com/files/266160/original/file-20190327-139349-1h40qtz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">An MRI image of the brain.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/mri-image-head-showing-brain-344282432">SpeedKingz/Shutterstock.com</a></span></figcaption></figure><p>Scientific success stories can sometimes occur when therapies being studied for one disease can be used to treat another.</p>
<p>In the case of the drug we have been <a href="https://ken-kosik.mcdb.ucsb.edu">studying in my lab</a>, this is especially important because it could be used to develop a drug for Alzheimer’s. This cancer drug, lonafarnib, may be able to rid the cell of abnormal tau proteins and the clumps of tau protein called tangles that, together with other abnormal proteins called senile plaques, are the <a href="https://www.nia.nih.gov/health/alzheimers">hallmarks of Alzheimer’s disease</a>. Plaques and tangles are two structures easily observed under the microscope in the brains of deceased Alzheimer’s patients. </p>
<p><a href="https://ken-kosik.mcdb.ucsb.edu/people/kenneth-kosik">I am neurologist</a> and a <a href="https://www.ncbi.nlm.nih.gov/pubmed?term=kosik%20ks">neurobiologist</a> and have been interested in the diseases associated with the tau protein for nearly three decades, first while I worked at the Harvard Medical School and Brigham and Women’s Hospital and now at the University of California, Santa Barbara, where I co-direct the <a href="https://www.nri.ucsb.edu">Neuroscience Research Institute</a>. </p>
<p>We used mice engineered to develop tau tangles, and showed in my lab that lonafarnib <a href="http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aat3005">prevents their formation</a>. This approach, called repurposing, is the use of a drug originally invented to treat one disease, but is unexpectedly effective in another. Because tau in the neurofibrillary tangles is a critical feature of Alzheimer’s, a disease that has risen to <a href="https://doi.org/10.1016/j.jalz.2018.06.3063">pandemic proportions worldwide</a>, I believe this repurposed drug should be a high priority for testing in clinical trials. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/0GXv3mHs9AU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">A simple explainer on Alzheimer’s and the tau and A-beta proteins.</span></figcaption>
</figure>
<h2>Preventing tangles</h2>
<p>The key component of neurofibrillary tangles is the tau protein, a normal brain protein that in the course of the disease aggregates into long rope-like structures and ultimately strangles neurons in disease. This transition from a normal protein to an aggregate is the focus of our research and using a repurposed drug was a useful way to probe the transition.</p>
<p>One thing that is exciting about repurposing this cancer drug is that testing has clearly demonstrated its safety in humans. Society does not currently have any medication that can modify or prevent Alzheimer’s – which underscores the importance of following our results from mice to patient testing. However, many details need to be worked out before a trial can proceed and the most appropriate study subjects chosen.</p>
<p>Nevertheless, it is now a good time to move promising drugs to the clinic given the <a href="https://www.statnews.com/2019/03/21/biogen-eisai-alzheimer-trial-stopped/">recent failures</a> of many drug trials for Alzheimer’s disease.</p>
<p>So how did we link a cancer drug with the tau protein? </p>
<p>The first step before even being aware of the cancer drug was a difficult and risky experiment we conducted that had a surprising outcome. We collected skin cells from patients with a form of dementia called <a href="https://www.nia.nih.gov/health/topics/frontotemporal-disorders">frontotemporal dementia</a> that has only neurofibrillary tangles but no senile plaques. In the absence of senile plaques, we cannot call this disease Alzheimer’s even though neurofibrillary tangles made of tau are a shared feature. </p>
<p>This disease simplified our quest because we didn’t have to worry about the plaques. But we believe the findings will certainly be relevant to Alzheimer’s disease especially as researchers increasingly appreciate the importance of the tangles in causing the dementia. </p>
<p>Furthermore, in the cases we studied, we knew the specific cause of the patients’ dementia; these patients all had mutations in their tau gene. We sampled and grew their skin cells in the lab using a specialized technique and then compared them with skins cells from patients with normal tau. We detected a gene, and the protein it produced – Rhes – that was abnormally turned on in the cells from patients with the tau mutations but not in the control cells. That was the ah-ha moment because the Rhes protein belongs to a family of proteins targeted by the cancer drug, lonafarnib.</p>
<p>Then came the mental leap, which makes science exciting. </p>
<h2>Targeting tau for the trash compactor</h2>
<p>Like most proteins, this one, Rhes, has multiple functions, and deciding which specific function to pursue requires both savvy and luck. In our case, we found a drug that lowered the level of the Rhes protein and enabled the abnormal tau protein to get directed into a cell compartment that degrades proteins. This compartment is called the lysosome, and it acts like a trash compactor. This organelle destroys tau before it can form tangles. </p>
<p>To test this drug we used genetically engineered mice that develop human tau tangles and then dementia. Such animals often run in circles. But when we fed these animals lonafarnib, the drug blocked the formation of the tau tangles in the brain and the abnormal behavior. </p>
<p>When tau tangles disrupt the normal brain activity, the mice are unable to build nests. But the mice receiving the drug proceeded with nest-building and other normal behaviors. Mice that were untreated all developed dementia. </p>
<p>Seeing these results and then replicating them several times were exhilarating moments and is the reward for many experiments that do not work. However, any student considering doing this type of research should have a comfort level with the long game.</p><img src="https://counter.theconversation.com/content/114135/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kenneth S. Kosik owns shares in ADRx and Minerva Pharmaceuticals. He receives funding from the NIH, The Edward N. & Della L. Thome Memorial Foundation and the Larry H. Hillblom Foundation.
</span></em></p>Not all drug development needs to start from scratch. Sometimes researchers discover that a drug developed for one disease can be used for another. Here a cancer drug may show promise for dementia.Kenneth S. Kosik, Professor of Neuroscience, University of California, Santa BarbaraLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1088092019-02-12T11:46:21Z2019-02-12T11:46:21ZTime for a Manhattan Project on Alzheimer’s<figure><img src="https://images.theconversation.com/files/253300/original/file-20190110-43517-1thkww2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Figuring out the pieces to the Alzheimer's puzzle.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/brain-degenerative-diseases-parkinson-alzheimer-puzzle-247872682">Naeblys/Shutterstock.com</a></span></figcaption></figure><p>Imagine if Alzheimer’s was treated like other common diseases. Instead of worrying about the prospect of slowly losing your memory, you might get a series of shots during middle age to prevent the onset of this neurological nightmare, just as we do to reduce the risk of flu. Or you could take a daily pill as many do to control their cholesterol or blood pressure.</p>
<p>That may sound improbable, given the <a href="https://doi.org/10.1186/alzrt269">long string of Alzheimer’s drugs</a> that have <a href="https://www.scientificamerican.com/article/why-alzheimer-s-drugs-keep-failing/">failed to work in clinical trials</a>, but I remain optimistic. As a <a href="https://www.utsouthwestern.edu/labs/diamond/about/meet-the-pi.html">physician-scientist</a> leading research into the causes of neurodegenerative diseases, I believe that we are making significant progress on uncovering the roots of Alzheimer’s. </p>
<p>Alzheimer’s is a neurodegenerative disease that has stymied researchers for years. The disease develops when two proteins – A-beta and tau – accumulate in the brain. A-beta builds up outside of nerve cells, and tau inside them. Decades of study suggests that A-beta somehow leads to the accumulation of tau, which is <a href="http://doi.org/10.1126/scitranslmed.3002369">what causes nerve cells to die</a>. This may explain why early treatments focusing exclusively on A-beta failed. These ideas have led to <a href="https://doi.org/10.1016/j.jalz.2018.02.018">new diagnostic criteria</a> that take into account these two proteins to make the definitive diagnosis. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/253293/original/file-20190110-43541-1b4l3eu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/253293/original/file-20190110-43541-1b4l3eu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/253293/original/file-20190110-43541-1b4l3eu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=281&fit=crop&dpr=1 600w, https://images.theconversation.com/files/253293/original/file-20190110-43541-1b4l3eu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=281&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/253293/original/file-20190110-43541-1b4l3eu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=281&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/253293/original/file-20190110-43541-1b4l3eu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=353&fit=crop&dpr=1 754w, https://images.theconversation.com/files/253293/original/file-20190110-43541-1b4l3eu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=353&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/253293/original/file-20190110-43541-1b4l3eu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=353&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Clumps of tau protein cause neurofibillatory tangles inside neurons. The A-beta protein forms clumps in between them. Together they destroy brain tissue.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/alzheimers-disease-309207956">joshya/Shutterstock.com</a></span>
</figcaption>
</figure>
<h2>Mechanistic studies take time but pay off</h2>
<p>As a scientist, I have always been fascinated by the molecular basis of disease, and as a physician I am committed to helping patients. <a href="https://www.utsouthwestern.edu/labs/diamond/">In my lab</a> at the University of Texas Southwestern Medical Center in Dallas, our group is focused on identifying structural changes in the tau protein that enable it to aggregate and cause disease. <a href="https://doi.org/10.7554/eLife.36584.001">Our work suggests that neurodegeneration begins</a> with a shape shift in the tau protein, which then forms toxic assemblies, or clumps, in the brain. These assemblies are mobile, and appear to transmit pathology between different groups of neurons causing disease progression. As tau appears to play the central role in destroying brain cells, and because lost neurons cannot be replaced, our researchers are working to develop tools to pick up the earliest signs of toxic tau. This may occur many years before cognitive symptoms become apparent.</p>
<p>If physicians can detect the disease-causing forms of tau, they will be able to diagnose the underlying disease before permanent loss of brain cells occurs, perhaps even before individuals know they have a problem. This requires that we develop better, more sensitive biomarkers that may facilitate this process, much like we now use hemoglobin A1C to diagnose incipient diabetes. </p>
<p>To do this we’ve pulled together an unconventional team with expertise in structural biology, biochemistry, cell biology, neurology and neuropathology to work side by side in our <a href="https://www.utsouthwestern.edu/education/medical-school/departments/alzheimers/">Center for Alzheimer’s and Neurodegenerative Diseases</a> (CAND). <a href="https://www.utsouthwestern.edu/labs/diamond/">Studies from my lab</a> have already contributed to the development of an <a href="https://www.alzforum.org/therapeutics/c2n-8e12">anti-tau antibody that is in clinical trials</a>. This antibody binds tau, and may <a href="https://news.abbvie.com/news/abbvie-initiates-phase-2-clinical-trial-programs-for-abbv-8e12-an-investigational-anti-tau-antibody-in-early-alzheimers-disease-and-progressive-supranuclear-palsy.htm">facilitate its clearance from the brain</a>. Full disclosure: I receive royalties through my former employer, Washington University in St. Louis, for my role in discovering this drug.</p>
<p>The approach at the CAND is much like the diverse group of engineers and physicists who were brought together during World War II for the <a href="https://www.history.com/topics/world-war-ii/the-manhattan-project">Manhattan Project</a> – the secret effort to create the first atomic bomb. Our multidisciplinary team marries discovery and engineering with the goal of developing diagnostic tools and personalized therapies that can stem the progression of Alzheimer’s and other neurodegenerative disorders. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/253298/original/file-20190110-43517-vmusoy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/253298/original/file-20190110-43517-vmusoy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/253298/original/file-20190110-43517-vmusoy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=494&fit=crop&dpr=1 600w, https://images.theconversation.com/files/253298/original/file-20190110-43517-vmusoy.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=494&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/253298/original/file-20190110-43517-vmusoy.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=494&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/253298/original/file-20190110-43517-vmusoy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=621&fit=crop&dpr=1 754w, https://images.theconversation.com/files/253298/original/file-20190110-43517-vmusoy.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=621&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/253298/original/file-20190110-43517-vmusoy.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=621&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The Manhattan Project was the secret government effort that created atomic weapons. Here seven atom bomb scientists look over a roentgenometer at the site of the test atom bomb explosion on Sept. 13, 1945. Pictured (l-r): Dr. Kenneth T. Bainbridge, Harvard; Dr. Joseph G. Hoffman, University of Buffalo; Dr. J. Robert Oppenheimer, California; Dr. Louis H. Hempelmann, Washington; Dr. Victor Weisskopf; Dr. Robert F. Bacher, Cornell University; and Dr. Richard W. Dodson of California.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Watchf-AP-A-NM-USA-APHSL40329-New-Mexico-Atom-/7e78c72cffe84e7bbd21db90ca988f06/3/1">AP Photo/KEYSTONE/Martial Trezzini</a></span>
</figcaption>
</figure>
<h2>The role of philanthropy</h2>
<p>Major philanthropists have realized the value of integrated research efforts to solve specific problems in science. They are pouring tens of millions of dollars into Alzheimer’s research. Our team at UT Southwestern was recently the recipient of a US$1 million award from the <a href="https://go.chanzuckerberg.com/NCN">Chan Zuckerberg Initiative</a>, set up by Facebook founder Mark Zuckerberg and his wife, Priscilla Chan. In all, the Chan Zuckerberg Initiative awarded more than $50 million to 17 investigators and nine scientific teams to launch a Neurodegenerative Challenge Network. This brings together scientists from diverse fields – biochemistry, genetics, neuropathology and computational science – who are taking a broad view of the disease by exploring multiple underlying causes of neurodegenerative diseases, even while researchers at CAND focus primarily on tau. </p>
<p>The challenge is growing more urgent. Alzheimer’s is a defining medical problem of our generation. <a href="https://www.cdc.gov/features/alzheimers-disease-deaths/index.html">More than 5 million Americans</a> are now afflicted, and that number is expected to reach nearly <a href="https://www.cdc.gov/features/alzheimers-disease-deaths/index.html">14 million by 2050</a> – threatening to overwhelm an already stressed health care system. </p>
<p>With support from the Chan Zuckerberg Initiative, we have integrated research across multiple different labs to try to develop a logical system to classify the various <a href="http://doi.org/10.1007/s00401-017-1717-7">subtypes of neurodegnerative diseases linked to tau</a>. This system is rooted in linking the three-dimensional structure of a single tau protein to its cellular effects, and correlating specific structures with particular <a href="https://doi.org/10.7554/eLife.37813.001">patterns of pathology</a>. One day we hope to extract tiny amounts of critical proteins from blood, or spinal fluid that bathes the brain, to predict the onset of specific diseases, and then intervene with a personalized treatment before damage is done.</p>
<p>We seek a “personalized” approach to diagnosis based on protein structure. This is analogous to how genetic information is now used to classify cancer. We hope to use this framework to identify patients at risk, so that we can monitor their responses to treatment, and ultimately, to decide who will benefit most from specific interventions. This ambitious plan will require sophisticated new tools to study protein structure, to analyze brain tissues, and to facilitate translation of these ideas to the clinic, all in close collaboration across very disparate scientific disciplines.</p>
<h2>We must continue to fund basic research</h2>
<p>While we think targeting tau aggregation and its spread through the brain is the best way to treat disease, it is unlikely to be the only effective one. New therapies are now making their way through clinical trials. These include drugs that <a href="https://www.alzforum.org/therapeutics/biib080">turn off the tau gene and block the protein’s production</a>. Multiple trials are using the body’s immune system to attack A-beta and tau proteins, and new biological information about how tau and A-beta cause pathology within cells may lead to complementary strategies. </p>
<p>Vigorous efforts such as the Chan Zuckerberg Initiative are providing a critical boost at a time when some <a href="https://doi.org/10.1038/nrd.2018.16">pharmaceutical companies have scaled back research</a> into brain disorders. This means that support from the federal government remains indispensable. The National Institutes of Health has <a href="http://doi.org/10.1126/science.aav2455">tripled its annual budget for research</a> into Alzheimer’s and related dementias since 2014, reaching $1.9 billion in the last fiscal year. </p>
<p>I can’t predict when we will have a treatment for Alzheimer’s. But I am confident that when it happens it will be based on discoveries made in academic research laboratories, just as scientists in previous generations produced vaccines for polio and effective drugs for HIV and hepatitis C. </p>
<p>A vaccine for Alzheimer’s? Gene editing seemed like science fiction 25 years ago, but now it’s <a href="https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm534611.htm">being used to save lives</a>. By shifting the paradigm on Alzheimer’s research, treatments for neurodegenerative diseases can also become reality.</p><img src="https://counter.theconversation.com/content/108809/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marc Diamond receives funding from the National Institutes of Health, the Department of Defense, the State of Texas, the Rainwater Charitable Foundation, the Cure Alzheimer's Fund and the Aging Minds Foundation.</span></em></p>Many pieces leading to Alzheimer’s disease have been identified. To put the pieces together, one scholar argues that the government should launch a Manhattan Project-scale effort to find a cure.Marc Diamond, Professor of Neurology and Neurotherapeutics, UT Southwestern Medical CenterLicensed as Creative Commons – attribution, no derivatives.