tag:theconversation.com,2011:/id/topics/tau-54604/articlesTau – The Conversation2023-10-17T19:03:53Ztag:theconversation.com,2011:article/2056282023-10-17T19:03:53Z2023-10-17T19:03:53ZNew technique uses near-miss particle physics to peer into quantum world − two physicists explain how they are measuring wobbling tau particles<figure><img src="https://images.theconversation.com/files/532985/original/file-20230620-21-sf8wvl.jpg?ixlib=rb-1.1.0&rect=464%2C501%2C4206%2C3241&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The Large Hadron Collider at CERN can be used to study many kinds of fundamental particles, including mysterious and rare tau particles.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/abstract-neon-circles-digital-fractal-black-royalty-free-image/1191907046?phrase=particle+physics&adppopup=true">Oxygen/Moment via Getty Images</a></span></figcaption></figure><p>One way physicists seek clues to unravel the mysteries of the universe is by smashing matter together and inspecting the debris. But these types of destructive experiments, while incredibly informative, have limits. </p>
<p>We are two scientists who <a href="https://www.colorado.edu/physics/dennis-perepelitsa">study nuclear</a> and <a href="https://www.phy.cam.ac.uk/staff/dr-jesse-liu">particle physics</a> using CERN’s Large Hadron Collider near Geneva, Switzerland. Working with an international group of nuclear and particle physicists, our team realized that hidden in the data from previous studies was a remarkable and innovative experiment. </p>
<p>In a new paper published in Physical Review Letters, we developed a new method with our colleagues for measuring <a href="https://doi.org/10.1103/PhysRevLett.131.151802">how fast a particle called the tau wobbles</a>.</p>
<p>Our novel approach looks at the times incoming particles in the accelerator whiz by each other rather than the times they smash together in head-on collisions. Surprisingly, this approach enables far more accurate measurements of the tau particle’s wobble than previous techniques. This is the first time in nearly 20 years scientists have measured this wobble, known as the <a href="https://doi.org/10.1088/1742-6596/912/1/012001">tau magnetic moment</a>, and it may help illuminate tantalizing cracks <a href="https://theconversation.com/the-standard-model-of-particle-physics-may-be-broken-an-expert-explains-182081">emerging in the known laws of physics</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/531776/original/file-20230613-26-1ofchy.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diagram showing a particle wobbling off of a vertical axis." src="https://images.theconversation.com/files/531776/original/file-20230613-26-1ofchy.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/531776/original/file-20230613-26-1ofchy.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=319&fit=crop&dpr=1 600w, https://images.theconversation.com/files/531776/original/file-20230613-26-1ofchy.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=319&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/531776/original/file-20230613-26-1ofchy.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=319&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/531776/original/file-20230613-26-1ofchy.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=401&fit=crop&dpr=1 754w, https://images.theconversation.com/files/531776/original/file-20230613-26-1ofchy.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=401&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/531776/original/file-20230613-26-1ofchy.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=401&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Electrons, muons and taus all wobble in a magnetic field like a spinning top. Measuring the wobbling speed can provide clues into quantum physics.</span>
<span class="attribution"><span class="source">Jesse Liu</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
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</figure>
<h2>Why measure a wobble?</h2>
<p>Electrons, the building blocks of atoms, have two heavier cousins called the <a href="https://www.britannica.com/science/subatomic-particle/Charged-leptons-electron-muon-tau">muon and the tau</a>. Taus are the heaviest in this family of three and the most mysterious, as they exist only for minuscule amounts of time.</p>
<p>Interestingly, when you place an electron, muon or tau inside a magnetic field, these particles wobble in a manner similar to how a spinning top wobbles on a table. This wobble is called a particle’s magnetic moment. It is possible to predict how fast these particles should wobble using the <a href="https://home.cern/science/physics/standard-model">Standard Model of particle physics</a> – scientists’ best theory of how particles interact.</p>
<p>Since the 1940s, physicists have been interested in measuring magnetic moments to reveal intriguing <a href="https://doi.org/10.1103/PhysRev.74.250">effects in the quantum world</a>. According to quantum physics, clouds of particles and antiparticles are constantly <a href="https://www.symmetrymagazine.org/article/july-2009/virtual-particles">popping in and out of existence</a>. These fleeting fluctuations slightly alter how fast electrons, muons and taus wobble inside a magnetic field. By measuring this wobble very precisely, physicists can peer into this cloud to uncover possible hints of undiscovered particles. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/531789/original/file-20230613-15-4hjd2s.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A chart showing the basic particles." src="https://images.theconversation.com/files/531789/original/file-20230613-15-4hjd2s.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/531789/original/file-20230613-15-4hjd2s.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=574&fit=crop&dpr=1 600w, https://images.theconversation.com/files/531789/original/file-20230613-15-4hjd2s.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=574&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/531789/original/file-20230613-15-4hjd2s.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=574&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/531789/original/file-20230613-15-4hjd2s.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=722&fit=crop&dpr=1 754w, https://images.theconversation.com/files/531789/original/file-20230613-15-4hjd2s.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=722&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/531789/original/file-20230613-15-4hjd2s.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=722&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Electrons, muons and taus are three closely related particles in the Standard Model of particle physics – scientists’ current best description of the fundamental laws of nature.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Standard_Model_of_Elementary_Particles.svg#/media/File:Standard_Model_of_Elementary_Particles.svg">MissMJ, Cush/Wikimedia Commons</a></span>
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<h2>Testing electrons, muons and taus</h2>
<p>In 1948, theoretical physicist Julian Schwinger first calculated how the quantum cloud <a href="https://doi.org/10.1103/PhysRev.73.416">alters the electron’s magnetic moment</a>. Since then, experimental physicists have measured the speed of the electron’s wobble to an extraordinary <a href="https://doi.org/10.1038/s41586-020-2964-7">13 decimal places</a>. </p>
<p>The heavier the particle, the more its wobble will change because of undiscovered new particles lurking in its quantum cloud. Since electrons are so light, this limits their sensitivity to new particles.</p>
<p>Muons and taus are much heavier but also far shorter-lived than electrons. While muons exist only for mere microseconds, scientists at Fermilab near Chicago measured the muon’s magnetic moment to <a href="https://news.fnal.gov/2021/04/first-results-from-fermilabs-muon-g-2-experiment-strengthen-evidence-of-new-physics/">10 decimal places</a> in 2021. They found that muons wobbled noticeably faster than Standard Model predictions, suggesting unknown particles may be appearing in the muon’s quantum cloud.</p>
<p>Taus are the heaviest particle of the family – 17 times more massive than a muon and 3,500 times heavier than an electron. This makes them much more <a href="https://doi.org/10.1103/PhysRevD.64.035003">sensitive to potentially undiscovered particles</a> in the quantum clouds. But taus are also the hardest to see, since they live for just a millionth of the time a muon exists.</p>
<p>To date, the best measurement of the tau’s magnetic moment was made in 2004 using <a href="https://home.cern/science/accelerators/large-electron-positron-collider">a now-retired electron collider</a> at CERN. Though an incredible scientific feat, after multiple years of collecting data that experiment could measure the speed of the tau’s wobble to only <a href="https://doi.org/10.1140/epjc/s2004-01852-y">two decimal places</a>. Unfortunately, to test the Standard Model, physicists would need a measurement <a href="https://doi.org/10.1142/S0217732307022694">10 times as precise</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/531773/original/file-20230613-29-zwf5pp.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram showing two particles nearly colliding." src="https://images.theconversation.com/files/531773/original/file-20230613-29-zwf5pp.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/531773/original/file-20230613-29-zwf5pp.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=319&fit=crop&dpr=1 600w, https://images.theconversation.com/files/531773/original/file-20230613-29-zwf5pp.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=319&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/531773/original/file-20230613-29-zwf5pp.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=319&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/531773/original/file-20230613-29-zwf5pp.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=401&fit=crop&dpr=1 754w, https://images.theconversation.com/files/531773/original/file-20230613-29-zwf5pp.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=401&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/531773/original/file-20230613-29-zwf5pp.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=401&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Instead of colliding two nuclei head-on to create tau particles, two lead ions can whiz past each other in a near miss and still produce taus.</span>
<span class="attribution"><span class="source">Jesse Liu</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Lead ions for near-miss physics</h2>
<p>Since the 2004 measurement of the tau’s magenetic moment, physicists have been seeking new ways to measure the tau wobble.</p>
<p>The Large Hadron Collider usually smashes the nuclei of two atoms together – that is why it is called a collider. These head-on collisions create a <a href="https://cds.cern.ch/record/2841509">fireworks display of debris</a> that can include taus, but the noisy conditions preclude careful measurements of the tau’s magnetic moment.</p>
<p>From 2015 to 2018, there was an experiment at CERN that was designed primarily to allow nuclear physicists to study <a href="https://home.cern/science/physics/heavy-ions-and-quark-gluon-plasma">exotic hot matter</a> created in head-on collisions. The particles used in this experiment were lead nuclei that had been stripped of their electrons – called lead ions. Lead ions are electrically charged and produce <a href="https://doi.org/10.1038/nphys4208">strong electromagnetic fields</a>. </p>
<p>The electromagnetic fields of lead ions contain particles of light called photons. When two lead ions collide, their photons can also collide and convert all their energy into a single pair of particles. It was these photon collisions that scientists used to <a href="https://doi.org/10.1103/PhysRevLett.121.212301">measure muons</a>.</p>
<p>These lead ion experiments ended in 2018, but it wasn’t until 2019 that one of us, Jesse Liu, teamed up with particle physicist Lydia Beresford in Oxford, England, and realized the data from the same lead ion experiments could potentially be used to do something new: measure the tau’s magnetic moment. </p>
<p><a href="https://doi.org/10.1103/PhysRevD.102.113008">This discovery was a total surprise</a>. It goes like this: Lead ions are so small that they often miss each other in collision experiments. But occasionally, the ions pass very close to each other without touching. When this happens, their accompanying photons can still smash together while the ions continue flying on their merry way. </p>
<p>These photon collisions can create a variety of particles – like the muons in the previous experiment, and also taus. But without the chaotic fireworks produced by head-on collisions, these near-miss events are far quieter and ideal for measuring traits of the elusive tau.</p>
<p>Much to our excitement, when the team looked back at data from 2018, indeed these lead ion near misses were creating tau particles. There was a new experiment hidden in plain sight!</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/532999/original/file-20230620-8426-na9es5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A long tube in an underground tunnel." src="https://images.theconversation.com/files/532999/original/file-20230620-8426-na9es5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/532999/original/file-20230620-8426-na9es5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/532999/original/file-20230620-8426-na9es5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/532999/original/file-20230620-8426-na9es5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/532999/original/file-20230620-8426-na9es5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/532999/original/file-20230620-8426-na9es5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/532999/original/file-20230620-8426-na9es5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&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 Large Hadron Collider accelerates particles to incredibly high speeds before trying to smash particles together, but not all attempts result in successful collisions.</span>
<span class="attribution"><a class="source" href="http://cds.cern.ch/record/1211045">Maximilien Brice/CERN</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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</figure>
<h2>First measurement of tau wobble in two decades</h2>
<p>In April 2022, the CERN team announced that we had found <a href="https://atlas.cern/updates/briefing/observation-taupair-heavy-ions">direct evidence of tau particles created</a> during lead ion near misses. Using that data, the team was also able to measure the tau magnetic moment – the first time such a measurement had been done since 2004. The final results were published on Oct. 12, 2023.</p>
<p>This landmark result measured the tau wobble to two decimal places. Much to our astonishment, this method tied the previous best measurement using only one month of data recorded in 2018.</p>
<p>After no experimental progress for nearly 20 years, this result opens an entirely new and important path toward the tenfold improvement in precision needed to test Standard Model predictions. Excitingly, more data is on the horizon. </p>
<p>The Large Hadron Collider just restarted <a href="https://home.cern/news/news/experiments/lhc-lead-ion-collision-run-starts">lead ion data collection on Sept. 28, 2023</a>, after routine maintenance and upgrades. Our team plans to quadruple the sample size of lead ion near-miss data by 2025. This increase in data will double the accuracy of the measurement of the tau magnetic moment, and improvements to analysis methods may go even further.</p>
<p>Tau particles are one of physicists’ best windows to the enigmatic quantum world, and we are excited for surprises that upcoming results may reveal about the fundamental nature of the universe.</p><img src="https://counter.theconversation.com/content/205628/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jesse Liu is supported by a Junior Research Fellowship at Trinity College, University of Cambridge. </span></em></p><p class="fine-print"><em><span>Dennis V. Perepelitsa receives research funding from the U.S. Department of Energy, Office of Science.</span></em></p>Physicists uncovered a new experiment hidden in old data from the Large Hadron Collider. Using this innovative approach, the team has unlocked an entirely new way to study quantum physics.Jesse Liu, Research Fellow in Physics, University of CambridgeDennis V. Perepelitsa, Associate Professor of Physics, University of Colorado BoulderLicensed 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>
<figure class="align-center zoomable">
<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>
<figcaption>
<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>
</figcaption>
</figure>
<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>
</figure>
<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/1690532021-10-15T13:02:09Z2021-10-15T13:02:09ZMore accurate way to predict who will develop Alzheimer’s disease – new study<figure><img src="https://images.theconversation.com/files/425779/original/file-20211011-23-1wqrw9g.jpg?ixlib=rb-1.1.0&rect=26%2C17%2C5964%2C3970&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/female-hand-trying-connect-missing-jigsaw-1457724410">Orawan Pattarawimonchai/Shutterstock</a></span></figcaption></figure><p>Beta-amyloid and tau are two proteins that serve useful functions in the brain, but in Alzheimer’s disease – the most common form of dementia – they go rogue and <a href="https://pubmed.ncbi.nlm.nih.gov/24493463/">destroy brain cells</a> (neurons). This happens when beta-amyloid forms clumps on the outside of neurons and tau forms tangles and destroys neurons from the inside. This destruction leads to the classic symptoms of Alzheimer’s disease: problems with memory and with thinking and reasoning.</p>
<p>Studies have shown that beta-amyloid accumulates in the brain <a href="https://www.nature.com/articles/nature08538">earlier than tau</a>, before any symptoms appear. But our <a href="https://www.nature.com/articles/s41380-021-01263-2">latest study</a>, published in the journal Molecular Psychiatry, shows that an early accumulation of tau in the brain is a better predictor of Alzheimer’s related memory decline than an accumulation of amyloid plaque.</p>
<p>Although these proteins are characteristic of Alzheimer’s, their relationship with the disease is not always straightforward. In some cases, the disease might occur even <a href="https://academic.oup.com/brain/article/139/9/2528/1744656">without beta-amyloid in the brain</a>. And beta-amyloid in a person’s brain does not necessarily mean they will <a href="https://pubmed.ncbi.nlm.nih.gov/23360977/">develop Alzheimer’s</a>. Still, insight into these proteins gives important information about the signs and progressions of most cases of Alzheimer’s disease. In other words, they are important biological signs, or “biomarkers”, of the disease.</p>
<p>However, until a few years ago, the levels of these proteins in a person with Alzheimer’s could only be measured after the person had died. Today, we can measure these levels in living people using two methods: examining a sample of cerebrospinal fluid (the clear liquid that surrounds the brains and spinal cord) taken with a lumbar puncture, and positron emission tomography (PET) brain scans. The latter uses a special dye called a “tracer” that stains the tau tangles so they show up on the scan.</p>
<p>With the fast progression of research in biomarkers, we are quickly getting better at measuring and detecting early signs of Alzheimer’s in patients. But we still need tests that can predict the development of the disease with greater accuracy. </p>
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<img alt="PET scan of the human brain." src="https://images.theconversation.com/files/426246/original/file-20211013-27-16m86kz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/426246/original/file-20211013-27-16m86kz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426246/original/file-20211013-27-16m86kz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426246/original/file-20211013-27-16m86kz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426246/original/file-20211013-27-16m86kz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426246/original/file-20211013-27-16m86kz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426246/original/file-20211013-27-16m86kz.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">
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<span class="caption">PET scan of the human brain.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/pet-ct-scan-human-brain-axial-1410637847">Utthapon wiratepsupon/Shutterstock</a></span>
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<p>Recent guidelines for the early detection of Alzheimer’s disease proposed that <a href="https://pubmed.ncbi.nlm.nih.gov/29653606/">biomarkers from PET and spinal fluid</a> were both equally accurate at predicting Alzheimer’s disease. But this view was later <a href="https://pubmed.ncbi.nlm.nih.gov/32398359/">questioned</a> by scientists when new evidence showed that biomarkers from PET and spinal fluid <a href="https://pubmed.ncbi.nlm.nih.gov/32398359/">do not always agree</a>. There is also a lack of long-term studies showing how the biomarkers are linked to the gradual loss of memory.</p>
<h2>Which method is best?</h2>
<p>Our study shows that the presence of beta-amyloid in the brain and changes in concentrations of beta-amyloid and tau (a specific form called pTau-181) in the spinal fluid can be detected early in the course of the disease, but they do not seem to have any correlation with later memory loss. In contrast, the presence of tau in the brain measured by PET turned out to be linked to a rapid decline of episodic memory – the memory of everyday events.</p>
<p>Episodic memory is often affected at an early stage of the disease, and our study suggests that looking for tau using PET scans is the best way to predict early stage Alzheimer’s. </p>
<p>Our results are based on brain imaging (PET) and spinal fluid analyses in a group of 282 participants comprising people with mild cognitive impairment, people with Alzheimer’s disease and healthy people (the control group). </p>
<p>Among these, 213 participants were also monitored for three years with tests of short-term memory related to daily events. PET scans showed that 16% of the participants had a buildup of tau. This was associated with them having more rapid memory decline than participants without tau accumulation, regardless of the beta-amyloid accumulation in the brain.</p>
<p>Tau accumulation in the brain (as shown by PET scan) was also more accurate than tau measured in spinal fluid at detecting a short-term memory decline. In other words, the tau spinal fluid test was negative in some cases, while the tau PET scan was positive for the same subject. This confirms that lumbar puncture and imaging methods are not always comparable. </p>
<p>Interestingly, over 30% of the participants with tau accumulation in the brain had no or little cognitive impairment at the start of the study, revealing how tau can accumulate at the early stage of the disease without showing ill effects and still predict the subsequent decline in short-term memory.</p>
<h2>Next-generation tracers</h2>
<p>Even though the tau PET turned out to be more accurate than other biomarkers in predicting a decline in short-term memory, the first-generation tau PET tracer used in our study has its limitations. </p>
<p>Any PET tracer, ideally, is supposed to bind only to the target molecule (tau) in the target organ (brain), but in the first-generation tracers, it also bound to unwanted structures that showed up in the scan. This is called “off-target binding”. Its presence can be <a href="https://pubmed.ncbi.nlm.nih.gov/27296779/">verified by post-mortem studies</a> on slices of brain where you can see where the tau tangles are.</p>
<p>In the future, more specific tau tracers (second generation) will hopefully minimise the off-target binding and provide better options to predict more accurately how the disease will play out.</p><img src="https://counter.theconversation.com/content/169053/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marco Bucci 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>PET scans using a special tracer can pick up ‘tau tangles’ in the brain.Marco Bucci, Postdoctoral Researcher, Karolinska InstitutetLicensed 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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<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/1531242021-01-18T14:53:54Z2021-01-18T14:53:54ZAlzheimer’s: new research shows a leap forward in identifying neurons vulnerable to the disease<figure><img src="https://images.theconversation.com/files/379228/original/file-20210118-19-v8cgqb.jpg?ixlib=rb-1.1.0&rect=39%2C0%2C5300%2C2999&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The loss of neurons leads to degeneration.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/active-nerve-cells-3d-illustration-617032409">adike/ Shutterstock</a></span></figcaption></figure><p>Alzheimer’s disease is a devastating condition that is currently unstoppable and incurable. The main cause of the disease is the loss of neurons and other brain cells in the brain – also know as degeneration. This degeneration is what leads to problems with memory and other cognitive functions.</p>
<p>Researchers can tell which neurons die first or exhibit increased vulnerability to Alzheimer’s disease based on where they’re located in the brain and what they look like. But they don’t know what genes or proteins these neurons express. Knowing these factors is important for recognising and identifying the changes in specific cells that happen when disease is present. </p>
<p>Now, a <a href="https://www.nature.com/articles/s41593-020-00764-7">recent study</a> has shown that neurons expressing a specific protein are more vulnerable to degeneration. Understanding which neurons are more vulnerable – and why – might allow researchers to develop targets for potential treatments in the future.</p>
<p>To conduct their study, scientists performed a post-mortem brain analysis on people who had Alzheimer’s disease. To see how far the disease had progressed, they began by looking for build-ups of the protein <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090074/">tau</a> in different parts of the brain. In people with Alzheimer’s disease, tau proteins aggregate in cells, which usually causes the cells to die. Tau accumulates differently in different brain areas, which is why some areas exhibit a greater degree of degeneration. </p>
<p>After identifying the disease progression, the researchers then focused their attention on two specific brain regions: the <a href="https://www.sciencedirect.com/topics/neuroscience/entorhinal-cortex">entorhinal cortex</a> and the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/superior-frontal-gyrus">superior frontal gyrus</a>. The entorhinal cortex is involved in <a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/hipo.450010102">memory</a>, while the superior frontal gyrus plays a role in functions associated with <a href="https://www.newscientist.com/article/dn9019-watching-the-brain-switch-off-self-awareness/">self-awareness</a>.</p>
<figure class="align-center ">
<img alt="A depiction of a tau protein buildup on a brain neuron." src="https://images.theconversation.com/files/379229/original/file-20210118-17-16it3ao.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/379229/original/file-20210118-17-16it3ao.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/379229/original/file-20210118-17-16it3ao.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/379229/original/file-20210118-17-16it3ao.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/379229/original/file-20210118-17-16it3ao.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/379229/original/file-20210118-17-16it3ao.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/379229/original/file-20210118-17-16it3ao.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">
<figcaption>
<span class="caption">Tau accumulates differently in different brain areas.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/death-neurons-aging-brain-proteins-3d-1492655510">Design_Cells/ Shutterstock</a></span>
</figcaption>
</figure>
<p>Tau accumulates in the entorhinal cortex in the early stages of Alzheimer’s disease, but doesn’t accumulate until later on in the superior frontal gyrus. By looking at two areas with different cell loss in different disease stages, scientists could look for differences in the same cell types. This could also potentially allow them to uncover what makes them vulnerable, and when they become vulnerable. </p>
<p>The researchers looked at the different types of neurons and cells in the entorhinal cortex, and examined how much tau they had accumulated, as well as what proteins these cells expressed. The researchers founds that a specific type of neuron – called excitatory neurons (which generate “action” signals in the brain) – were the most vulnerable of the cells examined. They found that these neurons exhibited a nearly 50% decline in their numbers during the early stages of Alzeimer’s disease. </p>
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Read more:
<a href="https://theconversation.com/microglia-the-brains-immune-cells-protect-against-diseases-but-they-can-also-cause-them-139232">Microglia: the brain’s 'immune cells' protect against diseases – but they can also cause them</a>
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<p>The researchers also found that on a molecular level, these excitatory neurons contained higher levels of one specific protein called RORB (retinoid-related orphan receptor beta). As this protein wasn’t detected in other cells, this shows that the genes and proteins a cell express may determine its vulnerability.</p>
<p>The protein RORB is involved in the development of different types of neurons, and is also a transcription factor – meaning it’s able to control the expression of other proteins in cells. This means that RORB can activate or deactivate certain pathways which may lead to disease. </p>
<p>The researchers then compared these RORB-vulnerable excitatory neurons to other excitatory neurons. They found differences in their genes – specifically those involved in how the synapses (which send and receive signals in the brain) form, as well as in signalling molecules (which help send messages in the brain). </p>
<p>To confirm that these excitatory neurons which express RORB are indeed more vulnerable to Alzheimer’s disease, the team then examined these neurons in the superior frontal gyrus. They also compared their findings against other studies. They found that in the superior frontal gyrus too, excitatory neurons were similarly vulnerable if they contained high levels of RORB. This finding shows that even in different disease stages and brain areas, neurons that showed the most vulnerability had high levels of RORB.</p>
<p>The researchers also looked at other types of neurons and cells to see if they had any changes. They found that only astrocytes – which play an important role in the brain, including <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348542/">regulating neuronal activity</a> and protecting the brain from <a href="https://pubmed.ncbi.nlm.nih.gov/11596126/">disease and infection</a> – showed changes during disease progression. The researchers found that astrocytes appeared to be more activated, which usually only happens when there is disease or infection present in the brain. </p>
<p>As this study only focused on brain samples taken from males with a specific Alzheimer’s disease-related gene, it’s difficult to know whether these findings will also be similar in women, or in people with different genetic backgrounds. However, this study does provide a better understanding of the cells which are most vulnerable in Alzheimer’s disease. This may be a stepping stone for better understanding why such vulnerability exists. Future studies focusing on RORB in neurons and its functions might produce exciting results, and hopefully exciting therapies.</p><img src="https://counter.theconversation.com/content/153124/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Eleftheria Kodosaki 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>Knowing what cells are more vulnerable could some day help researchers know why these cells are more vulnerable than others.Eleftheria Kodosaki, Research associate in neuroimmunology, Cardiff UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1318102020-04-14T09:26:57Z2020-04-14T09:26:57ZAlzheimer’s: the ‘switch-on moment’ discovered<figure><img src="https://images.theconversation.com/files/315498/original/file-20200214-10991-9dp8iy.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C7360%2C4561&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/retired-couple-holding-hands-looking-each-1272275779">LightField Studios/Shutterstock</a></span></figcaption></figure><p>The past three decades saw a dramatic improvement in our understanding of what brings about Alzheimer’s disease. Two proteins are thought to be responsible: amyloid and tau. The most widely accepted theory is that a critical level of amyloid in the brain triggers the build-up of the more toxic tau protein. This has led to several studies testing drugs and vaccines that remove amyloid and tau to see if they can improve or even prevent dementia. Results have been disappointing. </p>
<p>All studies in dementia patients have failed to show improvements, even if amyloid itself was affected. In a <a href="https://academic.oup.com/brain/article/142/7/2113/5510133">prominent case</a>, a vaccine given to patients was shown to have cleared the brain of amyloid of people who nonetheless died of profound dementia. </p>
<p>Over the same period, <a href="https://n.neurology.org/content/71/2/85.long">studies</a> in people destined to develop the condition because of a genetic mutation reported that the changes leading to dementia begin up to 25 years before any symptoms. One logical interpretation is that attempts to find a cure for dementia may have failed because the patients in drug trials were treated <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752906/">too late in the disease process</a>. </p>
<p>This new thinking led to new treatments being tested as early as possible, for example, at the stage of having widespread amyloid in the brain but no other signs of dementia – so-called preclinical dementia. These studies use methods such as spinal tap or positron emission tomography (a type of brain scan) to confirm that a person has a critical level of amyloid. But there is <a href="https://www.ncbi.nlm.nih.gov/pubmed/28567001">evidence</a> that already at this very early stage, potentially irreversible damage, such as loss of brain tissue, is occurring. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410966/">Researchers</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921038/">have gone further</a> <a href="https://www.jneurosci.org/content/38/19/4482">and shown that</a> people who are yet to reach the critical level of amyloid but are accumulating the protein at an accelerated rate, show early signs of dementia-related brain changes, such as changes to mental ability. </p>
<h2>Finding fast protein accumulators</h2>
<p>Our team wanted to know if such a group of “fast protein accumulators” can be identified among healthy ageing adults. The implication is that these people would be the ones who would benefit most from a drug that interferes with the dementia process, before any damage has set in. </p>
<p>To do this, we accessed two US studies that collected repeated spinal tap and amyloid brain scans for decades. We were able to demonstrate that some people are on a particularly aggressive course of build-up of either amyloid or tau, or both. Importantly, there seemed to be a “switch on” moment in the participants’ late 50s when the accumulation suddenly ramped up. </p>
<p>Having a genetic variant that is <a href="https://www.cell.com/neuron/pdf/S0896-6273(19)30083-2.pdf">well known</a> to predispose people to dementia (the e4 version of the APOE gene) made it more likely that the person would be on the aggressive protein-accumulation path and have their “switch on” moment five years earlier, compared with those without an APOE e4 gene version. </p>
<p>We found that the “switch on” moment happens at roughly the same age for both the amyloid and tau proteins. This contradicts the theory that “a brain full of amyloid” is needed to start the cascade leading to dementia. Instead, the processes that lead to dementia run concurrently. </p>
<p>Also, as our studies ran for decades, a number of people eventually developed memory problems. We found that a person that was accumulating both tau and amyloid fast was most likely to be diagnosed with dementia in the decades to follow.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/315500/original/file-20200214-11000-1h9e8en.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/315500/original/file-20200214-11000-1h9e8en.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/315500/original/file-20200214-11000-1h9e8en.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/315500/original/file-20200214-11000-1h9e8en.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/315500/original/file-20200214-11000-1h9e8en.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/315500/original/file-20200214-11000-1h9e8en.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/315500/original/file-20200214-11000-1h9e8en.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">
<figcaption>
<span class="caption">Proteins accumulating on a brain cell.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/death-neurons-aging-brain-proteins-3d-1492655510">Design_Cells</a></span>
</figcaption>
</figure>
<h2>Wearable devices</h2>
<p><a href="https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/dad2.12019">Our paper</a> shows that we now have the technology to identify people who are on a fast track to developing dementia. Still, it would not be practical to screen for these people by doing repeated spinal taps. Instead, we need to find cheap and easy-to-tolerate methods to predict who belongs to this fast track group of people. </p>
<p>We found that tests usually deployed in dementia studies (brain scans, clinic memory tests) were not useful in this respect. It is possible that so early on we need a whole different set of tests that show very minor changes in the way our brains function day to day. Examples of these could be wearable devices that show subtle changes in gait or disturbances in the quality of sleep. Apps that track how well we go about our use of digital technology over time (for example, how fast we are in finding the right word when texting) may also point to people whose brains are under strain. </p>
<p>A number of such digital technologies are being developed and, hopefully, in the not-too-distant future, we will have access to such solutions in both routine clinical practice as well as studies testing new treatments that delay or even prevent dementia.</p><img src="https://counter.theconversation.com/content/131810/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ivan Koychev received funding from Medical Research Council to complete the reported study. His time spent on the study was funded by the UK National Institute of Health Research and the Oxford Health Biomedical Research Centre.
Ivan receives consultancy fees for being an Advisory Board member for Mantrah Ltd, a company that develops an app aimed at supporting patients with dementia to adhere to their treatment plans.</span></em></p>We now have the technology to identify people who are on a fast track to developing dementia.Ivan Koychev, Senior Clinical Researcher, Dementia, University of OxfordLicensed 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>
<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">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.tag:theconversation.com,2011:article/1027062018-09-05T02:49:20Z2018-09-05T02:49:20ZDementia patients’ thinking ability may get worse in winter and early spring<figure><img src="https://images.theconversation.com/files/234957/original/file-20180905-45169-1713aem.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Thinking ability declines with age in those with dementia.</span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/tUyYnO_VdP0">Sam Wheeler/Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>The seasons may affect the memory and thinking abilities of healthy older adults. A new study suggests changes in cognitive function may be associated with the time of year, declining significantly in winter and early spring. We also see new cases of mild cognitive impairment and dementia in these seasons.</p>
<p>Published today in the journal <a href="https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002647#pmed.1002647.ref002">PLOS Medicine</a>, the study suggests fluctuations in memory and thinking performance across seasons are equivalent to an approximate four-year difference in age. That is, the performance of people given memory and thinking tests in the summer and autumn would be equivalent to those about four years younger than when tested in spring and winter.</p>
<p>The authors also found new cases of <a href="https://www.alz.org/alzheimers-dementia/what-is-dementia/related_conditions/mild-cognitive-impairment">mild cognitive impairment</a> (a transitional diagnosis given prior to a dementia diagnosis) and dementia were 30% more likely in spring and winter relative to summer and autumn. </p>
<p>Dementia is when a person experiences a significant deterioration in memory and thinking abilities (cognitive function), noticed by themselves or a significant other. This goes together with a decline in their ability to perform everyday tasks such as paying bills, keeping on top of work, or even keeping themselves oriented to time and place, as well as mood changes.</p>
<p>These findings suggest there may be a need for more dementia care resources and community awareness during these colder months.</p>
<h2>What the research showed</h2>
<p>A group of researchers from Canada and the United States sought to answer the question of whether the season might influence poorer cognition in healthy adults, as well as those with dementia. Their questioning was based on previous findings in other areas of human biology, such as <a href="https://jamanetwork.com/journals/jamapsychiatry/article-abstract/493246">seasonal affective disorder</a> (depression associated with seasonal changes) and <a href="https://www.cambridge.org/core/journals/psychological-medicine/article/seasonality-of-symptom-onset-in-firstepisode-schizophrenia/BAFC8A432C269852168600809A6A5163">first-episode schizophrenia</a>. These findings suggest an association with time of year. </p>
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Read more:
<a href="https://theconversation.com/seasonal-affective-disorder-why-you-feel-under-the-weather-937">Seasonal Affective Disorder: why you feel under the weather</a>
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<p>Researchers have suggested these seasonal peaks in psychosis could be associated with stress and other social factors that may correspond with seasonal trends.</p>
<p>In the current study, the authors investigated data on around 2,700 healthy older adults from Chicago and around 500 dementia patients from Toronto. They found individuals tested in the months of July to October (summer-autumn in the Northern Hemisphere) displayed better performance than those tested in other months. This was true for both healthy adults and those with a dementia diagnosis.</p>
<p>They also found working memory (the ability to hold things in mind for a short time, such as memorising someone’s phone number) and speed of processing (how quickly someone is able to perform a task such as drawing a clock on a piece of paper) were most affected by the season. And the findings did not change if they accounted for the person’s mood, level of physical activity, sleep quality, time of day of testing, or thyroid integrity. </p>
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<a href="https://images.theconversation.com/files/234964/original/file-20180905-45143-1wizpia.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/234964/original/file-20180905-45143-1wizpia.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/234964/original/file-20180905-45143-1wizpia.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/234964/original/file-20180905-45143-1wizpia.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/234964/original/file-20180905-45143-1wizpia.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/234964/original/file-20180905-45143-1wizpia.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/234964/original/file-20180905-45143-1wizpia.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/234964/original/file-20180905-45143-1wizpia.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">The study authors argue being less physically active during the colder months wouldn’t make a difference to the findings.</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/78hTqvjYMS4">Matthew Bennett/Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
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<p>So, the authors argued this association was unlikely to be driven by outside environmental factors such as lower physical activity in winter months. Other confounding influences cannot be discounted. These include season-related injuries or pain such as arthritis, social isolation, changes in exposure to pollution or unaccounted-for biological factors. </p>
<h2>Biological changes</h2>
<p>Researchers also found changes in the biology of Alzheimer’s disease associated with the season. Alzheimer’s disease is a form of dementia mainly defined by two hallmark pathologies in the brain – a buildup of proteins called amyloid and tau. </p>
<p>In the purest sense, Alzheimer’s disease can only be diagnosed after death. But it is possible to measure levels of amyloid and tau during life using an imaging technique known as positron emission tomography (PET). This technology is still largely confined to research.</p>
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Read more:
<a href="https://theconversation.com/what-causes-alzheimers-disease-what-we-know-dont-know-and-suspect-75847">What causes Alzheimer’s disease? What we know, don’t know and suspect</a>
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<p>Amyloid is known to become abnormal very early in the disease process. Examining spinal fluid extracted from participants, researchers found amyloid protein fluctuations in the cerebrospinal fluid of healthy older adults became more abnormal during winter months.</p>
<p>While the authors could not provide an explanation for this cyclical pattern in amyloid levels in the spinal fluid, they pointed out this aligned closely with memory and thinking patterns seen in the same adults.</p>
<h2>How should we read the findings?</h2>
<p>These findings are interesting and are some of the first in this area. But they need to be interpreted with a degree of scientific caution. </p>
<p>One major drawback is they’re predicated entirely on cross-sectional data. That is, people were not specifically followed during each season across the year to determine changes in their cognition. Researchers analysed data already available. </p>
<p>Further, these studies rely entirely on Northern Hemisphere data. This might not be applicable to the Southern Hemisphere.</p>
<p>These findings are correlational, so it cannot be said a particular season causes cognitive decline – it is merely associated with it. What one can imply from these data is more dementia care resources and community awareness may be needed during these months. </p>
<p>At a population level, these findings suggest a trend towards poorer cognitive performance and greater incidence of dementia cases in spring and winter, which might not simply be a case of “the winter blues”. These findings remind us to be mindful of dementia in our community, and that some may be particularly vulnerable at certain times of the year. </p>
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Read more:
<a href="https://theconversation.com/getting-the-temperature-just-right-helps-people-with-dementia-stay-cool-97374">Getting the temperature just right helps people with dementia stay cool</a>
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<p>What remains to be done are studies specifically set up to measure cognitive performance in individuals throughout each season to determine if there really is something to feeling a bit mentally sluggish in the winter months.</p>
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<p><em>We are looking for volunteers to take part in our ongoing study to understand brain health and ageing. If you are interested, and between the ages of 40 and 65, please head to <a href="https://www.healthybrainproject.org.au/">The Healthy Brain Project</a>.</em></p>
<p><em>This article originally stated the research was published in the journal PLOS One. This has been corrected to PLOS Medicine.</em></p><img src="https://counter.theconversation.com/content/102706/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Rachel Buckley receives funding from the National Health and Medical Research Council and Australian Research Council with a Dementia Research Fellowship. </span></em></p>Have you noticed your thinking ability drops during winter and spring? A new study of healthy adults and dementia patients found cognitive function declines in the colder months.Rachel Buckley, Research Fellow, Harvard Medical School, Research Fellow, Florey Institute of Neuroscience and Mental HealthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/972222018-06-05T14:20:13Z2018-06-05T14:20:13ZAlzheimer’s disease: why insulin is a new suspect<figure><img src="https://images.theconversation.com/files/220508/original/file-20180525-51121-x2obzx.jpg?ixlib=rb-1.1.0&rect=5%2C65%2C992%2C690&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/616016807?src=7owY9wu_qe2QyPEjTj1mHg-1-57&size=medium_jpg">Naeblys/Shutterstock.com</a></span></figcaption></figure><p>Johnson and Johnson <a href="http://www.pharmatimes.com/news/janssen_pulls_plug_on_alzheimers_candidate_1235957">recently announced</a> that it was halting a clinical trial for a new Alzheimer’s drug after safety issues emerged. This latest failure adds to the dozens of large, costly clinical trials that have shown no effect in treating this devastating disease. </p>
<p>The growing list of failures should give us pause for thought – have we got the causes of Alzheimer’s all wrong? </p>
<p>In the first analysis of the disease, the German physician, <a href="https://en.wikipedia.org/wiki/Alois_Alzheimer">Alois Alzheimer</a>, noted odd changes in the brain of a patient who died of the condition. Alzheimer identified two kinds of protein aggregates that are not found in younger brains: plaques that are found between brain cells and tangles that are found inside brain cells. </p>
<p>Later research identified the proteins that made up the plaques as amyloid and those that form the tangles as tau. What these structures actually do is still under debate. </p>
<h2>Unheeded warning</h2>
<p>Alzheimer advised scientists not to jump to the conclusion that these proteins caused the disease. Unfortunately, his caution was ignored, and over the years it has become gospel that the build up of these proteins causes Alzheimer’s disease. </p>
<p>One problem is that it’s not possible to test, in a scientific experiment, if this theory is correct. Only in recent years has technology been developed that can test what these proteins do, and it is clearly not what scientists previously assumed. For example, genetically engineered mice that accumulate human amyloid in their brains <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579350/">show only mild impairment</a>. But the pharmaceutical industry made up its mind a long time ago that amyloid is the culprit, and this has been the target for Alzheimer’s drugs ever since. </p>
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<img alt="" src="https://images.theconversation.com/files/221545/original/file-20180604-175400-11fdvza.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/221545/original/file-20180604-175400-11fdvza.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=890&fit=crop&dpr=1 600w, https://images.theconversation.com/files/221545/original/file-20180604-175400-11fdvza.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=890&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/221545/original/file-20180604-175400-11fdvza.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=890&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/221545/original/file-20180604-175400-11fdvza.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1118&fit=crop&dpr=1 754w, https://images.theconversation.com/files/221545/original/file-20180604-175400-11fdvza.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1118&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/221545/original/file-20180604-175400-11fdvza.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1118&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">Alois Alzheimer’s warning was ignored.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/w/index.php?curid=11653065">Wikimedia Commons</a></span>
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<p>The aim of these drugs is to reduce the levels of amyloid in the brain, either by slowing down the formation of amyloid or by removing it from the brain. Both approaches have been tested many times now using different techniques and drug types. None of these trials have shown any effects, and some large drug companies, <a href="https://uk.reuters.com/article/us-pfizer-alzheimers/pfizer-ends-research-for-new-alzheimers-parkinsons-drugs-idUKKBN1EW0TN">including Pfizer</a>, have abandoned this area of research altogether. </p>
<p>The continued failure of new drugs to make a difference has to be interpreted as evidence that the amyloid protein is not the cause of Alzheimer’s disease. Some companies have changed their target to the tau protein. But again, drugs companies are assuming that a single protein is the cause of the disease. </p>
<h2>Promising new avenues</h2>
<p>Perhaps it is time to rethink the disease altogether. One approach is to look for genes that increase the risk of developing the disease. The problem with this approach is that there are <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362699/">surprisingly few</a> of these genes, and they are rare. Alzheimer’s does not appear to be driven by gene mutations, so this approach does not shed new light on the underlying processes.</p>
<p>Another option is to look at the risk factors for developing Alzheimer’s. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405821/">One of these</a> is type 2 diabetes. Clearly, diabetes is very different from Alzheimer’s disease, so what’s the connection?</p>
<p>In diabetes, insulin becomes less effective at controlling blood sugar levels. But insulin does a lot more than just control blood sugar; it is a “growth factor”. Neurons (brain cells) are very dependent on growth factors, and if they don’t get enough, they die.</p>
<p>The loss of insulin’s growth factor effects in the brain appear to make neurons vulnerable to stress and reduce the brain’s ability to repair damage that accumulates over time. (Neurons live as long as we do, so there is a lot of time for damage to accrue.) </p>
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<img alt="" src="https://images.theconversation.com/files/221776/original/file-20180605-119867-1wyb8mu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/221776/original/file-20180605-119867-1wyb8mu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=337&fit=crop&dpr=1 600w, https://images.theconversation.com/files/221776/original/file-20180605-119867-1wyb8mu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=337&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/221776/original/file-20180605-119867-1wyb8mu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=337&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/221776/original/file-20180605-119867-1wyb8mu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/221776/original/file-20180605-119867-1wyb8mu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/221776/original/file-20180605-119867-1wyb8mu.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">If brain cells don’t get enough growth factor, they die.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/576832348?src=UP7lmOBrypM6oThYf5anGQ-1-0&size=medium_jpg">whitehoune/Shutterstock.com</a></span>
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<p>When looking at brain tissue taken from deceased Alzheimer’s patients, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314463/">researchers found</a> that insulin lost its effectiveness as a growth factor, even in people who were not diabetic. This observation suggests that diabetes drugs might be an effective treatment for people with Alzheimer’s. Some experiments showed <a href="https://www.ncbi.nlm.nih.gov/pubmed/29402504">impressive results</a> in animal studies, and several clinical trials have started. </p>
<p>Testing these drugs in animal models of another neurodegenerative disorder, Parkinson’s disease, also showed impressive effects, and <a href="https://www.ncbi.nlm.nih.gov/pubmed/24662192">two</a> <a href="https://www.ncbi.nlm.nih.gov/pubmed/28781108">clinical trials</a> in Parkinson’s patients showed good protective effects. In one of the trials – a pilot study – the patients who received the diabetes drug did not get any worse for two years while the control group, who received a standard treatment for Parkinson’s, deteriorated significantly. The other trial, a larger trial with a placebo control, confirmed this result and showed no deterioration in the drug group during the 12 months of study.</p>
<p>To see any protective effect in the brain in a clinical trial is completely new, and it supports the new theory that Alzheimer’s and Parkinson’s disease are caused, at least in part, by a lack of growth factor activity in the brain. These new theories bring a fresh view on how these diseases develop and increase the likelihood of developing a drug treatment that makes a difference.</p><img src="https://counter.theconversation.com/content/97222/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Christian Holscher receives funding from The Cure Parkinson's Trust, The Alzheimer's Society</span></em></p>Alzheimer’s drug development tends to focus on protein aggregates in the brain. Perhaps that’s why they’ve all failed.Christian Holscher, Professor of Neuroscience, Lancaster UniversityLicensed as Creative Commons – attribution, no derivatives.