What you can do to prevent Alzheimer’s | Lisa Genova
How many people here would like to liveto be at least 80 years old?Yeah. I think we all havethis hopeful expectationof living into old age. Let’s project out into the future,to your future “you’s,”and let’s imagine that we’re all 85. Now, everyone look at two people. One of you probably hasAlzheimer’s disease. Alright, alright. And maybe you’re thinking,“Well, it won’t be me. “Then, OK. You are a caregiver. So — so in some way,this terrifying diseaseis likely to affect us all. Part of the fear around Alzheimer’sstems from the sensethat there’s nothing we can do about it. Despite decades of research, we stillhave no disease-modifying treatmentand no cure. So if we’re lucky enoughto live long enough,Alzheimer’s appears to beour brain’s destiny. But maybe it doesn’t have to be. What if I told you we couldchange these statistics,literally change our brain’s destiny,without relying on a cureor advancements in medicine?Let’s begin by looking atwhat we currently understandabout the neuroscience of Alzheimer’s. Here’s a pictureof two neurons connecting. The point of connection,this space circled in red,is called the synapse. The synapse is whereneurotransmitters are released. This is where signals are transmitted,where communication happens. This is where we think,feel, see, hear, desire . . . and remember. And the synapseis where Alzheimer’s happens. Let’s zoom in on the synapseand look at a cartoon representationof what’s going on. During the businessof communicating information,in addition to releasing neurotransmitterslike glutamate into the synapse,neurons also release a small peptidecalled amyloid beta. Normally, amyloid beta is cleared awaymetabolized by microglia,the janitor cells of our brains. While the molecular causesof Alzheimer’s are still debated,most neuroscientists believethat the disease beginswhen amyloid beta begins to accumulate. Too much is released,or not enough is cleared away,and the synapse beginsto pile up with amyloid beta. And when this happens, it binds to itself,forming sticky aggregatescalled amyloid plaques. How many people hereare 40 years old or older?You’re afraid to admit it now. This initial step into the disease,this presence of amyloidplaques accumulating,can already be found in your brains. The only way we could be sure of thiswould be through a PET scan,because at this point,you are blissfully unaware. You’re not showing any impairmentsin memory, language, or cognition . . . yet. We think it takes at least 15 to 20 yearsof amyloid plaque accumulationbefore it reaches a tipping point,then triggering a molecular cascadethat causes the clinicalsymptoms of the disease. Prior to the tipping point,your lapses in memorymight include things like,”Why did I come in this room?”or “Oh . . . what’s his name?”or “Where did I put my keys?”Now, before you allstart freaking out again,because I know half of you did at leastone of those in the last 24 hours –these are all normal kinds of forgetting. In fact, I would argue that these examplesmight not even involve your memory,because you didn’t pay attentionto where you put your keysin the first place. After the tipping point,the glitches in memory,language and cognition are different. Instead of eventually findingyour keys in your coat pocketor on the table by the door,you find them in the refrigerator,or you find them and you think,”What are these for?”So what happens when amyloid plaquesaccumulate to this tipping point?Our microglia janitor cellsbecome hyper-activated,releasing chemicals that causeinflammation and cellular damage. We think they might actuallystart clearing awaythe synapses themselves. A crucial neural transport proteincalled “tau” becomes hyperphosphorylatedand twists itselfinto something called “tangles,”which choke off the neuronsfrom the inside. By mid-stage Alzheimer’s,we have massive inflammation and tanglesand all-out war at the synapseand cell death. So if you were a scientisttrying to cure this disease,at what point would you ideallywant to intervene?Many scientists are betting bigon the simplest solution:keep amyloid plaquesfrom reaching that tipping point,which means that drug discovery is largelyfocused on developing a compoundthat will prevent, eliminate, or reduceamyloid plaque accumulation. So the cure for Alzheimer’s will likely bea preventative medicine. We’re going to have to take this pillbefore we reach that tipping point,before the cascade is triggered,before we start leavingour keys in the refrigerator. We think this is why, to date,these kinds of drugs have failedin clinical trials –not because the science wasn’t sound,but because the people in these trialswere already symptomatic. It was too late. Think of amyloid plaques as a lit match. At the tipping point, the matchsets fire to the forest. Once the forest is ablaze,it doesn’t do any goodto blow out the match. You have to blow out the matchbefore the forest catches fire. Even before scientists sort this out,this information is actuallyreally good news for us,because it turns out that the way we livecan influence the accumulationof amyloid plaques. And so there are things we can doto keep us from reachingthat tipping point. Let’s picture your riskof Alzheimer’s as a see-saw scale. We’re going to pilerisk factors on one arm,and when that arm hits the floor,you are symptomaticand diagnosed with Alzheimer’s. Let’s imagine you’re 50 years old. You’re not a spring chicken anymore,so you’ve accumulatedsome amyloid plaques with age. Your scale is tipped a little bit. Now let’s look at your DNA. We’ve all inherited our genesfrom our moms and our dads. Some of these genes will increase our riskand some will decrease it. If you’re like Alice in “Still Alice,”you’ve inherited a rare genetic mutationthat cranks out amyloid beta,and this alone will tipyour scale arm to the ground. But for most of us, the genes we inheritwill only tip the arm a bit. For example, APOE4 is a gene variantthat increases amyloid,but you can inherit a copy of APOE4from mom and dadand still never get Alzheimer’s,which means that for most of us,our DNA alone does not determinewhether we get Alzheimer’s. So what does?We can’t do anything about getting olderor the genes we’ve inherited. So far, we haven’t changedour brain’s destiny. What about sleep?In slow-wave deep sleep, our glial cellsrinse cerebral spinal fluidthroughout our brains,clearing away metabolic wastethat accumulated in our synapseswhile we were awake. Deep sleep is likea power cleanse for the brain. But what happens if you shortchangeyourself on sleep?Many scientists believethat poor sleep hygiene might actuallybe a predictor of Alzheimer’s. A single night of sleep deprivationleads to an increase in amyloid beta. And amyloid accumulationhas been shown to disrupt sleep,which in turn causesmore amyloid to accumulate. And so now we havethis positive feedback loopthat’s going to acceleratethe tipping of that scale. What else?Cardiovascular health. High blood pressure, diabetes,obesity, smoking, high cholesterol,have all been shown to increase our riskof developing Alzheimer’s. Some autopsy studies have shownthat as many as 80 percentof people with Alzheimer’salso had cardiovascular disease. Aerobic exercise has been shownin many studies to decrease amyloid betain animal models of the disease. So a heart-healthyMediterranean lifestyle and dietcan help to counterthe tipping of this scale. So there are many things we can doto prevent or delaythe onset of Alzheimer’s. But let’s sayyou haven’t done any of them. Let’s say you’re 65;there’s Alzheimer’s in your family,so you’ve likely inherited a gene or twothat tips your scale arm a bit;you’ve been burning the candleat both ends for years;you love bacon;and you don’t run unlesssomeone’s chasing you. Let’s imagine that your amyloid plaqueshave reached that tipping point. Your scale arm has crashed to the floor. You’ve tripped the cascade,setting fire to the forest,causing inflammation, tangles,and cell death. You should be symptomatic for Alzheimer’s. You should be having troublefinding words and keysand remembering what I saidat the beginning of this talk. But you might not be. There’s one more thing you can doto protect yourselffrom experiencingthe symptoms of Alzheimer’s,even if you have the full-blown diseasepathology ablaze in your brain. It has to do with neural plasticityand cognitive reserve. Remember, the experienceof having Alzheimer’sis ultimately a result of losing synapses. The average brain hasover a hundred trillion synapses,which is fantastic;we’ve got a lot to work with. And this isn’t a static number. We gain and lose synapses all the time,through a processcalled neural plasticity. Every time we learn something new,we are creating and strengtheningnew neural connections,new synapses. In the Nun Study,678 nuns, all over the age of 75when the study began,were followed for more than two decades. They were regularly givenphysical checkups and cognitive tests,and when they died, their brainswere all donated for autopsy. In some of these brains, scientistsdiscovered something surprising. Despite the presence of plaquesand tangles and brain shrinkage –what appeared to beunquestionable Alzheimer’s –the nuns who had belongedto these brains showed no signsof having the diseasewhile they were alive. How can this be?We think it’s because these nunshad a high level of cognitive reserve,which is a way of saying that they hadmore functional synapses. People who have more yearsof formal education,who have a high degree of literacy,who engage regularlyin mentally stimulating activities,all have more cognitive reserve. They have an abundanceand a redundancy in neural connections. So even if they have a diseaselike Alzheimer’scompromising some of their synapses,they’ve got many extra backup connections,and this buffers them from noticingthat anything is amiss. Let’s imagine a simplified example. Let’s say you only know one thingabout a subject. Let’s say it’s about me. You know that Lisa Genovawrote “Still Alice,”and that’s the only thingyou know about me. You have that single neural connection,that one synapse. Now imagine you have Alzheimer’s. You have plaques and tanglesand inflammationand microglia devouring that synapse. Now when someone asks you,“Hey, who wrote ‘Still Alice?'”you can’t remember,because that synapseis either failing or gone. You’ve forgotten me forever. But what if you had learned more about me?Let’s say you learnedfour things about me. Now imagine you have Alzheimer’s,and three of those synapsesare damaged or destroyed. You still have a wayto detour the wreckage. You can still remember my name. So we can be resilientto the presence of Alzheimer’s pathologythrough the recruitmentof yet-undamaged pathways. And we create these pathways,this cognitive reserve,by learning new things. Ideally, we want these new thingsto be as rich in meaning as possible,recruiting sight and soundand associations and emotion. So this really doesn’t meandoing crossword puzzles. You don’t want to simply retrieveinformation you’ve already learned,because this is like travelingdown old, familiar streets,cruising neighborhoods you already know. You want to pave new neural roads. Building an Alzheimer’s-resistant brainmeans learning to speak Italian,meeting new friends,reading a book,or listening to a great TED Talk. And if, despite all of this, you aresomeday diagnosed with Alzheimer’s,there are three lessons I’ve learnedfrom my grandmotherand the dozens of people I’ve come to knowliving with this disease. Diagnosis doesn’t meanyou’re dying tomorrow. Keep living. You won’t lose your emotional memory. You’ll still be ableto understand love and joy. You might not rememberwhat I said five minutes ago,but you’ll remember how I made you feel. And you are more than whatyou can remember. Thank you.