Science and Music in Support of SHIELDing the Brain: A Clinical Conversation with Rudolph Tanzi,PhD,and Robert Rountree,MD

Dr. Rudolph Tanzi received his BSc and BA in Microbiology and History at the University of Rochester, followed by his PhD in Neuroscience at Harvard University. Since then, Dr. Tanzi has been a Professor of Neurology at Harvard Medical School and the Director of the Genetics and Aging Research Unit and Vice-Chair of Neurology at Massachusetts General Hospital. Dr. Tanzi has co-discovered various genes involved in Alzheimer's disease and is trying to identify drugs and other compounds that can prevent neuroinflammation. Dr. Tanzi has written Super Brain and Super Genes with Deepak Chopra, MD, and is also an avid musician and songwriter who performs and records with Joe Perry and Aerosmith.

Robert Rountree: What led you down the path that you have taken? Was there something that happened when you were growing up that was the genesis of all this? How did you decide between medicine and being a rock musician?

Rudolph Tanzi: Neither of my parents had the opportunity to go to college. My father was a baker, and my mom was originally a medical secretary. My mom then began doing medical transcription for doctor in a R.I. Hospital, and eventually both of my parents pioneered what was really one of the first outsourced medical transcription services in the country, back in the 1960s. As a teenager, I started getting access to reading medical histories and transcripts, since I would count lines on the page, as they charged by the line. This was my summer job as a kid—reading case records. So, I always had an interest in medicine, and I always thought I was going to be a clinician. I was interested in the eyes and ophthalmology.

However, over time, I got more interested in music. My dad was really into music, and he got me a Hammond B3 organ. He let me hear Jimmy Smith, so I switched from the accordion to the Hammond B3 organ. At a young age (17 years), I had the opportunity to play for a while with Ritchie Blackmore from Deep Purple. Because of this, I was invited to play at some high levels. However, in the summer of 1976, at 17 years of age, my 45-year-old father died suddenly of a heart attack on the golf course. So, I went to college. In college at that time, the genetic revolution was just starting—the whole recombinant DNA, genetic engineering revolution. And I was at a school that was really at the center of it. The University of Rochester probably had the most exciting recombinant DNA and genetic engineering work going on in the mid-1970s.

During my time in school, I was still playing with a band. Eventually, after graduating, however, I decided it was time to get a real job. I had also decided that I was more interested in genetics and research than I was in becoming a clinician. At the time, James Gusella, PhD, was looking for a postdoctoral fellow. I convinced him that I knew how to do everything that he needed done to set up his lab, and he hired me instead of a postdoc. Dr. Gusella was trying to set up a lab to find human genetic markers for locating disease genes. At the time, no one had done it yet.

So, now I was working in the lab by day and playing in a band by night. I was getting very little sleep—something I would not advise now. During this time, we were the first to find a disease gene using genetic markers isolated from the human genome. We found the Huntington's disease gene after isolating just a handful of the first genetic variances in the genome. The odds against what we did so quickly in this pioneering project were astronomically high. That paper, published in Nature in 1983, ¹ really was the milestone that set off the need for the Human Genome Project. Our findings made it appear to be possible to use variations in the human genome as markers to find genes for diseases that had no known biochemical basis or known protein defects. This was the very first disease gene mapping success. We now know what the Huntington's disease gene does, although scientists are still figuring out how to fix it. If you look at the Smithsonian Institute's Human Genetics Timeline (https://unlockinglifescode.org/timeline), they begin with Mendel and move up to Miescher on inherited “nuclein,” then on to Franklin, Watson, and Crick, and then to Nirenberg for the genetic code and Sanger for DNA sequencing in 1977. From there, they jump right up to us, the first time a disease gene was found using genetics, and then onward to the Human Genome Project.

This research led me to pursue Alzheimer's disease. As a backdoor route, I decided I wanted to map a chromosome from end to end using genetic markers. I picked the smallest chromosome, chromosome 21, so that I would get done faster. Also, chromosome 21 is duplicated in Down's syndrome, and people with Down's syndrome go on inevitably to get more Alzheimer's pathology than the average person. I wildly speculated, as a student at Harvard Medical School by then doing my doctoral degree, that there would be a gene on chromosome 21 that causes Alzheimer's, and it was going to make the amyloid plaques. Of course, I was told that was way too much speculation for a project, but I was pretty dogged, and it turned out to be right. So, I found the first Alzheimer's gene in the summer of 1986, and it was the gene that makes the amyloid plaque. ² I named it APP, the amyloid precursor protein. To this day, it is still the number-one drug target in Alzheimer's disease.

From there, I just kept on course finding Alzheimer's genes and creating model systems, understanding how the mutations cause the disease, and then trying to translate that into novel therapies, novel drugs. In the end, I co-discovered two other Alzheimer's genes, the presenilins, in 1995. ³ In addition, I discovered the Wilson's disease gene in 1993. ⁴ I was also a key player in the discovery of the first amyotrophic lateral sclerosis (ALS) gene, the first Lou Gehrig's gene, in 1995. However, most of what I would do is take the genes, find the mutations, make the model systems, and try to come up with new drugs and therapies.

In 2010, I gave a TED Medicine talk, in the same session as Deepak Chopra, MD, on how to help aging in a healthy way. After I spoke, I met Deepak in the men's room. The last thing you expect at a urinal is Deepak Chopra turning to you and saying, “So tell me, is the brain a noun or a verb?” I said, “Well, I think it is more of a verb, but let us take this outside.” So, we started talking, and the next thing you know, we wrote the book Super Brain. ⁵ We also wrote the book Super Genes, ⁶ both of which became best sellers. I then got very much into the more complementary, alternative side of what we can do for people now with lifestyle interventions, supplements, and the like while we are waiting for these miracle drugs to come online, which seem to be taking forever. This led me to now, where Deepak and I have our third book coming out in January 2018 called The Healing Self following up on the Super Brain and Super Genes books.

Dr. Rountree: When you first met Deepak Chopra, were you a meditator? Also, was he interested in your focus of genetics and molecular biology?

Dr. Tanzi: I was a meditator. I was, and still am, a big follower of Dr. Carlos Castaneda. I was very much into the methods that Dr. Castaneda talked about in his later books before he died, such as tensegrity movements (advanced yoga poses for mobilizing energy in the body) and lucid dreaming—in general, practicing the idea of lowered expectations, minimizing self-importance and expectation, maximizing awareness of abstract clues, and focusing on intuition. I was already thinking along those lines, so when I met Dr. Chopra, it was not a big stretch to become more and more interested in the integrative medicine side. At the same time, he was interested in my field. That is why we were able to write the books Super Brain, Super Genes, and The Healing Self so easily. I would say that since then, he has returned a little bit more toward being mainly interested in consciousness and the more esoteric and metaphysical side. I am interested in this as well, but as a scientist, if I can't measure something, I cannot approach it with anything but a belief system. I can talk in groups about consciousness and the like, but to me, that becomes more philosophy and not science, although it can turn into science once there is something to quantify. In science, you have to make the jump to where you actually generate data and measure effects. So, in the lifestyle pathways and alternative medicine pathways, I did work with Deepak to develop ways to quantify and measure the benefits of lifestyle interventions, such as meditation.

Deepak and I had a paper on looking at transcriptomic changes in the genome following a controlled clinical trial of meditation. We had another study using meditation in combination with an Ayurvedic diet and yoga, looking at effects on gene expression, metabolomics, lipidomics, and the microbiome. ^7,8 So, I think using a multi-omics approach, we can start quantifying the effects of lifestyle choices.

This research led us to start the Mass General Institute for Brain Health, aimed at carrying out hardcore measuring of effects of lifestyle interventions and nonmedical, nonconventional medicine methods of intervention, with clinical assessment, biomarkers, imaging, and also a lot of multi-omics measurements, transcriptomics, epigenomics, metabolomics, the microbiome, et cetera. We are just getting the Institute going now. Originally, it involved Dr. Chopra. However, he has since decided not to participate, and instead work more along the lines of consciousness, world peace, and what is going on in the world. Now that he has turned 70, he is thinking that for the next decade, he wants to do more far-reaching stuff that goes beyond science. Science just takes a long time. Science is tedious. I think that he is deciding his time would be better spent meditating, speaking, educating, and teaching. I am continuing the Institute without him, but it did start with our collaboration. We will keep it going.

Dr. Rountree: Has doing all this work with consciousness and meditation affected your view of genes as being less deterministic?

Dr. Tanzi: Yes, that is the whole point of Super Genes. You are dealt a deck of genes with variants that predispose you to certain diseases, but a minority of those gene mutations guarantee disease. The vast majority of mutations either increase or decrease the risk for disease, which means lifestyle plays a big role. In other words, nurture plays as much a role as nature.

So, that is why we wrote Super Genes. Your parents may give you the clay, but you sculpt it—and there is a lot of room to sculpt it. You may not be able to change the color of the clay, or the consistency of the clay, but you get to sculpt it. Only in a few cases is the clay already pre-sculpted.

So, in terms of maintenance of brain health, when you take on the right kinds of habits, meaning the four major categories—diet, exercise, sleep, and stress management, you can change the programming of the expression of your genes. We know that epigenetic changes can lead to chemical modifications that wire in certain gene expression programs. These modifications may be either bad or good for you, depending on what you are doing. For example, some “junk food” is going to wire in a gene expression program with epigenetics where you are chemically modifying genes with acetylation and methylation that is not necessarily good for you. ⁹ It might drive inflammation in the body, for example. However, if you change a habit from a junk food diet to more of a vegetarian or Mediterranean diet, organic food diet, with more probiotics, fiber, et cetera, then after a couple of months, you are going to undo the chemical modifications of the bad program and redo new modifications at the epigenetic level, with new methylation and demethylation patterns, and new acetylation/deacetylation patterns that favor a different gene expression program that is better for you.

So, the idea is that your habits begin with your intention, which begins with your brain and the choices you mindfully make every day. But in the end, they are wired in your genes and epigenetics, and that is determining your health. So, that is how Super Brain and Super Genes combine.

Dr. Rountree: We have a growing epidemic of people with Alzheimer's disease, as well as widespread access to genetic testing. A lot of people come to see me and feel that they are doomed because they are homozygous for the APOE4 gene and worry that it is a death sentence. What would you say to people like that?

Dr. Tanzi: Approximately 2% of people are APOE4 homozygous, and 20% are going to have one APOE4 allele. I am getting inundated with calls and e-mails from people who are freaking out because they carry one or two E4 alleles after finding out from direct-to-consumer DNA services. It is getting to the point now where as part of this new Institute for Brain Health, we are working with the Mass General Memory Disorders Unit to create a protocol to help people address their risk.

If someone carries an E4 allele, we will soon be offering additional genetic testing to ask whether you have other factors that mitigate or exacerbate risk. If someone is very worried, we can talk about imaging for amyloid pathology, which is what E4 leads to. Even though there is nothing we can do about it at the medicinal level, we can look at biomarkers in addition to imaging that might suggest that someone is beginning Alzheimer's pathology 10–15 years before symptoms might come around.

More than anything, we want to offer suggestions to these people about what they can do with their lifestyle to mitigate their risk, even if they carry an E4 allele. By the way, we have people with two E4 alleles in our database who are in their 80s or older and never got Alzheimer's disease. Double E4 is not a death sentence.

When we tell people about the four categories that I mentioned earlier, we use an acronym called SHIELD. We SHIELD our brain. I highlight these categories in detail in Super Genes. S stands for sleep, at least eight hours a night. H is to handle stress, manage stress, meditate if you can. I stands for interact, stay socially engaged. E is for exercise, at least take a brisk walk for an hour a day. If someone has a wrist device, try for 8,000 or 10,000 steps. L is to learn new things. This involves more than brain games, but making new synapses. Watch a documentary, brush your teeth with the other hand, put your pants on with the other leg first. Take a new route home during your commute. Learn something new online. Listen to a show that is teaching you things. Just learn new things. When you make new synapses, you also strengthen existing synapses and create new pathways for recalling information in memories. In the end, Alzheimer's disease is a disease of synaptic loss. So, I always advise people that when they are about to retire, they need to build up synaptic reserve by learning new things, just like building up financial reserves.

The last one is D for diet. In this case, we recommend the Mediterranean diet. I am a vegetarian myself, but in the end, it is about watching the fats and sugars. We also have a number of supplements that I take that still require clinical trials before we can say anything definitive about them, but they seem to be helpful. I share these sets of supplements that I take with others, telling them that we do not have the hard science yet to say that they are going to prevent Alzheimer's definitely. That would be a very long trial to do. However, these are supplements that do various good things.

With regards to exercise, this is about inducing the birth of new stem cells in the hippocampus, the short-term memory area of the brain affected in Alzheimer's. Exercise also reduces neuro-inflammation, a big killer in the disease. It also helps to reduce amyloid plaque. The same goes for sleep. A deep sleep reduces inflammation and amyloid plaque. ^10,11

We let people know this, and we use this SHIELD acronym. If someone has an E4, SHIELD becomes more of an obligation than an option.

Dr. Rountree: You brought up an interesting point about diet. There seems to be some divergent thinking here. Some people say to eat a diet more like a Mediterranean diet, with more plants and less meat. Then there are the paleo people who are saying that a ketogenic diet is the best diet for Alzheimer's. The paleo diet loads people up with coconut oil and tries to get their ketones going. What are your thoughts about those divergent viewpoints?

Dr. Tanzi: First of all, the paleo diet emphasizes meat and protein. The paleo diet was a diet of a people that lived until they were 25 years old. So, that is fine if someone wants to do that. Personally, I do not understand why we want to mimic the diet of people who died before 30 years of age. Maybe I am being too crass about that, but I do not think that there are any good data that say red meat is good for health. There are many ways to get protein. Everybody has a story, but you have to remember that a lot of people are just trying to sell books with trendy new diets. You have got to separate the wheat from the chaff. The best thing is just a sound diet, where the gut microbiome is being looked after, with probiotics and fiber, and watching fats and sugars.

Personally, I do not agree with a strictly ketogenic diet because it is a fatty diet. There are many ways that cells can get energy. They can get it from sugar, which in the end leads to inflammation. They can get it from fat, which in the end will lead to inflammation. They can get it from NAD-plus precursors. Personally, I take vitamins such as nicotinamide riboside, which is a NAD-plus precursor, because that is a route to cellular energy and ATP that does not require fats such as coconut oil or sugar. In the end, the idea is that cells have enough energy, the gut microbiome is happy, and there is enough protein and fat to feed your body. We do not want to overdo calories.

I do not think that there is any magic with this. I do not think we can say grain is bad for your brain or grain is going to kill you. The key is all food, even healthy ones, in moderation. Things come and go all the time. A new thing is that tomatoes are bad for you, which I just don't get. In the end, what usually wins is just sound information on a balanced diet where there is not too much of one thing and processed junk foods are avoided.

Dr. Rountree: What about omega-3 fats?

Dr. Tanzi: Omega-3s are very important, and most of us do not get enough. Since I do not eat fish, and I do not do fish oil because I am concerned about the quality control of heavy metals and heavy metal contamination of fatty fish and fish oil, I do an algae-based omega-3 containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). I think that a high intake of DHA and EPA is a great way to help fight inflammation in the brain, and it is part of my recommended supplement list. I don't think anyone knows exactly how much should be used, and because I am not a nutritionist, I would not make a recommendation. However, I take a relatively high amount: DHA 600 mg and EPA 300 mg.

Dr. Rountree: What about coconut oil? Do you think there is potential benefit from that, or medium-chain triglyceride (MCT) oil in general?

Dr. Tanzi: I think there is a potential benefit of MCTs. However, in the end, coconut oil is fat. So, too much coconut oil is probably not going to be good in the end. The jury is very much out on Alzheimer's disease and coconut oil. If you increase the energy intake in a patient with Alzheimer's, synaptic activity will be increased, and there can be a bit more interaction. However, it doesn't mean you're necessarily stopping the disease process.

I have received many e-mails and letters from people telling me that if they give their dad an ice-cream cone, suddenly he can speak coherently again. It is energy. We can get energy anaerobically through coconut oil and MCTs, but are we really helping the brain? It is possible that coconut oil is helpful because it is an energy source that does not require sugar. This provides excess energy to cells. In Alzheimer's disease, cells are under attack by amyloid plaque and inflammation. The more energy they have available to them, the more they might survive. An anaerobic energy source gives the cells a fighting chance to survive and do their jobs. I personally choose to do it with nicotinamide riboside, which I mentioned earlier. That is because it is not a fat- or sugar-related source of energy. Energy is good for cells. Upping cellular energy is good for you.

There was a paper that just came out that showed that when the TREM2 gene, one of the Alzheimer's genes, is turned off in microglial cells, they could not clear amyloid particularly well, and they were becoming neuroinflammatory instead, shooting out cytokines and free radicals. ¹² When they upped the energy of those cells artificially with a substrate to ATP, the cells, despite the lack of TREM2, started clearing amyloid again and came out of the neuroinflammatory profile. Anything that provides energy to a cell is going to do the same thing, whether it is an ice-cream cone, coconut oil, or an NAD-plus precursor.

Dr. Rountree: There is a medical food called Axona ^® that the Food and Drug Administration (FDA) approved for Alzheimer's. Can you discuss that?

Dr. Tanzi: I think Nestle bought Axona^®. It is mainly MCTs. It is the same idea as coconut oil. I thought four years ago the FDA told Accera they could not market it as medical food anymore. From what I remember, Accera, the makers of Axona^®, was told in 2013 that they couldn't call it a medical food. The company decided to test it as a drug. However, it failed to show any benefit in a Phase III clinical trial. The people who push coconut oil do not mention this—that Phase III trials directly using MCTs failed. ¹³ I think it is fine for people to take what they want to take, like I do. However, in the end, we have to draw the line between when we can say that we know that it works because there is clear evidence with significant p-values versus “I just think it is good for me.”

In fact, most of the supplements I take every day, I take just because I feel they are good for me, but I do not know they work. So, when I give this information to people, I just let them know what I take. I don't tell them that it will help them—only that I take them because my personal opinion is that these are good for me and make me feel better. It could be placebo effect—who knows?

Dr. Rountree: I have heard you talk about your Alzheimer's-in-the-dish model. Can you describe that?

Dr. Tanzi: Alzheimer's-in-the-dish is the nickname of a model that I use. Mice are a very bad model for Alzheimer's disease. So, in 2014, we published in Nature a report of a 3D neural cell culture system using human neurons made from stem cells grown in a mini-brain organelle in a petri dish. ^14,15 We can add into that culture the microglial cells to bring in the neuroinflammatory component. We can then use that system to test every known drug rapidly, which we have been doing, as well as every known supplement that we can get our hands on, including natural product libraries. Many of the natural products that are safe, as far as we know, that came out of that system, I have incorporated into my own daily regimen.

Dr. Rountree: Could you list some of those?

Dr. Tanzi: I take a concentrated form of cat's claw with oolong tea. As I said earlier, I take nicotinamide riboside and omega-3s. I also take vitamin B12 as methylcobalamin and vitamin D-3. Because I am on Lipitor^® (atorvastatin), I also take some coenzyme Q10. I take curcumin for knee pain, although curcumin does not get into the brain very well. I also take ashwagandha to help remove amyloid plaques from the brain, but only at night because it makes me a little sleepy.

I use my dish model because the mouse model is so poor. In mice, we have a good model for amyloid plaque, but not for Alzheimer's itself. In mice, the plaques do not lead to the neuron-killing tangles, the other main pathology of Alzheimer's. In fact, it is the lack of tangles in the mouse model that led to the debate about whether amyloids cause Alzheimer's disease in humans because in mice they do not. In mice, amyloid plaques lead eventually to inflammation and cognitive decline, but they do not lead to tangles. In the mid-1980s, Dr. George Glenner was the first one to propose the amyloid hypothesis. He said that Alzheimer's disease is the most common of the amyloidoses. He suggested that the amyloid was responsible for neurotoxic tangles and inflammation. ¹⁶

However, then we discovered the first Alzheimer's genes. When those genes were put into mice and there were no tangles, it led to debate. This led to probably the most referenced paper in the field: the amyloid cascade hypothesis. This hypothesis suggests that it takes a long time, with many steps, to go from amyloid to tangles, and that mice do not live long enough for that to happen.

It turns out that the hypothesis is all wrong. The lack of tangles was just because they were mice. If you have human neurons in a mini-brain organoid in a dish, and you have them make amyloid, they make tangles right afterward. The tangles follow the amyloid. If you stop the amyloid, the tangles go away. There is no 10-step cascade from amyloid to tangles as proposed to explain the failure to recapitulate the disease in mice. Plaques can be made in the mini-brain in the dish within six weeks. Full bona fide tangles appear two weeks later. If you stop the plaques, you stop the tangles, period.

In our dish model, ashwagandha shows some effects in blocking the ability of amyloid to cause tangles. In mice, it actually exports amyloid from the brain using the LDL receptor-like protein. ¹⁷ This is something that we cannot do in our model system. However, we are building a 3D blood–brain barrier model around the brain in a dish now where we will be able to test that.

Dr. Rountree: I also remember you mentioning that you had some benefit from cromolyn. Is that still consistent?

Dr. Tanzi: In 2008, we discovered the Alzheimer's gene called CD33. We learned over time that this controls neuroinflammation. It is a type of on/off switch for neuroinflammation in the microglial cells. ¹⁸ Normally, the microglial cells are clearing away plaque and cleaning up the brain, especially during deep sleep. During this time, the glymphatic system is at work, and microglial cells are cleaning up. It is evolutionarily programmed into the microglial cells that if neurons die, it is probably meningitis or encephalitis or something where they have to protect the area. At this time, microglial cells convert from housekeepers and cleaners into soldiers. They start producing free radicals and cytokines that cause neuroinflammation.

CD33 is the gene that turns on for this to happen. The more CD33 that is turned on in the microglial cell, the more it becomes a soldier, killing neurons around it by friendly fire versus a housekeeper cleaning up amyloid to protect the neurons. Thus, we have been looking for drugs and supplements that basically keep those microglial cells out of that neurotoxic or neuroinflammatory state.

You asked about cromolyn. This was one of the best hits we got. It is an old asthma drug. We are working with a company called AZ Therapies, with whom I have now taken a position as head of their scientific advisory board. For transparency, I also took equity with the company. I have shares. Now the company is doing a Phase III trial on cromolyn in Alzheimer's patients.

Dr. Rountree: Phytochemicals such as quercetin and luteolin appear to mimic the effects of cromolyn on stabilizing mast cells. Do you think they would have an effect, or do you know?

Dr. Tanzi: We only found one supplement in our screening that mimicked the effects of cromolyn. Right now, I am not at liberty to say what it is. It is very hard to get, and it comes from a Chinese flower. So, we only have one hit that mimics cromolyn from the natural products that we have tested. I have not directly tested quercetin and luteolin.

Dr. Rountree: Can we talk a bit about the latest research on the function of beta-amyloid? I uncovered an interview with you and The New York Times from about 15 years ago. At the time, you were very optimistic that one of these amyloid-clearing drugs would be the answer. Yet, it seems like it has not quite gone the way we had hoped. Now, we have new research coming out showing that it is an antimicrobial peptide such as cathelicidin.

Dr. Tanzi: Fifteen years ago, we did not know that amyloid plaques begin in the brain 15 years before symptoms. We did not know that they are the match and that tangles are the brush fires. We now know that we can live with a lot of plaques and tangles and not get Alzheimer's. It is not until the brain reacts to those brush fires, and ensuing cell death, with inflammation, that we fully go down the slippery slope.

So, like I said, the plaques are the match, and the tangles are the brush fires. Bangs to the head can also be the match. However, once those brush fires turn into a forest fire, or neuroinflammation, that is when the symptoms occur. The disease begins 15 years before symptoms or pathology.

The crazy thing is we do not diagnose Alzheimer's disease until there are symptoms. Think about how absurd that would be if we did the same with cancer or heart disease. Imagine if we told somebody who has a neoplastic cell and a tiny tumor that they do not have cancer yet because there are no symptoms. Imagine if we told them that we would wait for organ failure and for them to be writhing in pain, the symptoms of cancer, before we treated them with a tumor-suppressive drug. This is what we are doing with amyloid drugs.

Now we know you have to hit amyloid plaques 15 years before symptoms. If you hit the plaques in patients who have the disease with symptoms, it is like putting out a forest fire by blowing out the match. If we are able to hit very-early-stage mild patients, it is possible to maybe provide some benefit. I think the drug aducanumab suggests that is possible. ¹⁹ We are screening for drugs that can safely bring amyloid levels down.

I have a TEDx talk, where I talk all about this process. At the end, Chris Mann comes onstage, and we play our Alzheimer's anthem together, Remember Me. It is kind of cool.

Right now, the FDA will not cover amyloid imaging following drug use because they say it is not actionable. However, if someone has known high amyloid levels, they might be willing to kick SHIELD into high gear. Or they might take some ashwagandha, cats claw, omega-3s, and nicotinamide riboside.

Meanwhile, others and I are going after drugs that lower amyloid but don't wipe it out. Amyloid is an antimicrobial peptide. ²⁰ It is being made in the brain properly in response to viruses and bacteria that trigger its formation. It is part of the brain's innate immune system, such that when the A-beta peptide sees a virus or bacteria, it binds to the carbohydrate on the surface. It then agglutinates the microbes, forms oligomers, and then eventually fibrils, or what is called a nanonet, trapping those microbes so they cannot hit neurons or glial cells. This process has been known for a long time, and these peptides were the precursors to antibodies. Individuals with mutations that knock out antimicrobial peptides such as LL-37 do not live past the age of two years. These are the first line of defense against incoming pathogens—viral, bacterial, fungal, and even some cancer cells. The proteins agglutinate them and then wrap them in a little ball of amyloid. And that is why so many antimicrobial peptides are associated with amyloids.

What is new is that beta-amyloid in the brain is one of those amyloids that are caused by an antimicrobial peptide just trying to protect the organ, in this case the brain, from a microbial infection. This new paradigm that we have introduced is very radical, but our data are very strong. ²¹ We spent five years from the first paper to the second paper. We went from in vitro to animal models showing that microbes very rapidly induce plaque formation, and the plaques are being formed to protect the brain against the microbes.

Dr. Rountree: So, for clinicians that are working with people at risk of Alzheimer's disease, should we be doing a lot of investigation to look for evidence of infectious agents such as herpesvirus (HHV-6) or candida species infections—things that could be spurring production of amyloid? Is this a worthwhile pursuit?

Dr. Tanzi: I think it is worthwhile. We have a paper that is under review that shows that various types of viruses are abundant in the brain of Alzheimer's versus controls. We have carried out what is called the Brain Microbiome Project where we are actually mapping which viruses are found in the brain. We are asking whether amyloid is the means by which those viruses are captured and turned to protect the brain. We have a list of various viruses that are actually resident in the brain and are lying in a dormant state integrated in the genome, and they can be activated. Then, when they are activated and viral particles are made, the amyloid is formed. The viral particles actually induce the amyloid formation, and then the amyloid traps those viruses. So, we are actually sequencing the inside of plaques from autopsied brains to see what types of viruses or bacteria are trapped there.

This research is still in the early days, but we are moving beyond a proof of concept where we already published in mice, fruit flies, nematodes (Caenorhabditis elegans), and in the Alzheimer's-in-the-dish model that viruses rapidly induce amyloid. The amyloid is induced to be formed by the microbe so that they can trap the microbe and protect the organ. That is how antimicrobial peptides work, and A-beta peptide in beta-amyloid plaques are part of that system for the brain.

So, the question now is which microbes in the brain are doing this? That is why we started the Brain Microbiome Project. We are now trying to discover which are the most common viruses and bacteria that are inducing amyloid plaques as a defense mechanism of the immune system of the brain.

Dr. Rountree: Is it worth doing antiviral antibody panels on every patient with cognitive impairment at this time?

Dr. Tanzi: Not yet. However, it could be soon. I think that infection—low-grade infection—is going to play a much bigger role in this disease than we thought. It is going to be through the pathway of amyloid to tangles to inflammation. Our next step is to determine which viruses, bacteria, or fungus we have to target. And if our dreams come true, some day we will vaccinate against the most common offenders that are getting activated in the brain, or maybe bacteria that are activated in the brain through a compromised blood–brain barrier, for example, subsequent to a neurovascular event or to age. We can start trying to either vaccinate against those microbes, or maybe even use passive immunotherapy directly against those microbes.

Once triggered, amyloid does cause the tangles and cell death and inflammation. I think the Alzheimer's-in-the-dish model has put the debate that this is the case to rest. However, if we could go as a prequel to that and stop the need for the amyloid by hitting the microbes themselves, then that would be the ultimate form of primary prevention, better than primary prevention on the amyloid.

Dr. Rountree: Can you discuss chronic traumatic encephalopathy? I have heard you say that it is not an amyloid disease.

Dr. Tanzi: So, in 2012, Lee Goldstein and I published a study in Science Translational Medicine showing that the pathology of CTE is tangles and microglial activation and inflammation. ²² We also discovered that it was the bobble-head effect. So, if you want to help folks who have experienced a bomb blast in the battlefield, or football players who have had one too many concussions or traumatic brain injuries, you really have to target tangles and inflammation.

When I said that for Alzheimer's disease plaques are the match and tangles are the brush fire, in CTE it is still tangles and inflammation, but the match is bangs to the head and bobble-head effect versus amyloid. So, amyloid is the slow route to tangles and inflammation and dementia. Bangs to the head are a faster route to tangles and inflammation.

CTE prevalence based on the Whole Brain Bank at BU shows that 9% of the brains they received have CTE. However, there is ascertainment bias. In other words, there is a reason why those brains are being sent to BU. So, if you take that 9% and divide minimally by five for ascertainment bias, you are down to about 2% of the population. In fact, 2% is the number of APOE4 homozygotes in the population. I do not know if this has been formally looked at, but it is interesting to speculate that maybe most of the CTE cases are APOE4 homozygotes. However, I do not know that. I think it needs to be looked at.

This information also tells us that CTE prevalence in the NFL is highly hyped up by the headlines, but on the other hand, keeping players safe is very important. I have personally worked with the New England Patriots over the last season to help consult on brain health for them. I think that we just have to stay on top of it. We have to keep track of how many concussions a player has had. If they have had multiple concussions, their risk goes up, and it is a case-by-case basis, player-by-player basis. Eventually, I think we will bring genetics into it as well.

Dr. Rountree: Are there specific dietary recommendations you have for ball players?

Dr. Tanzi: I recommend the same supplements that I recommend for myself and family and friends. Everything is aimed at minimizing inflammation and tangle and plaque formation. You know, and SHIELD.

The New England Patriots are a model team in terms of SHIELD. They emphasize sleep. They emphasize stress. They emphasize, of course, exercise. They emphasize diet. They are a very proactive team. I am very impressed with the Patriots and how they do this. I think the NFL could learn a lot from them.

Dr. Rountree: Do you think nicotinamide riboside has potential in that regard?

Dr. Tanzi: I do. I think nicotinamide riboside should be seriously considered for those who engage in sports where there may be head injuries. Yes.

Dr. Rountree: If people want to follow your work, what is the best way to keep track of what you are doing?

Dr. Tanzi: I don't have my own Web site. I have been too busy to do it. So, I have my books. I have papers under review for publication. One paper is on the mechanism by which exercise induces neurogenesis and stops neuroinflammation in the brain—a very detailed molecular paper on that. We have a new paper about the viral components of the brain that are driving amyloid as an antimicrobial process. We have ongoing studies on supplements. And we have my amyloid drugs that are in development going into clinical trials. So, things are busy.

As I mentioned, I also have a new book coming out with Dr. Chopra in January 2018 called The Healing Self. This book is about mind over matter, psycho- and neuro-immunology, the power of the brain and placebo to bring health, basically a how-to book for enabling your mind to bring you good health.

The book goes over the science behind it and then gives day-by-day recommendations on what you can do, much of it around SHIELD, basically to maximize the healing powers of your mind over your body. So, that is the third book that is coming out.

Dr. Rountree: This has been very informative. In closing, it is interesting that now there is a lot of work being done using music to heal Alzheimer's. Are you still involved in music, and is your music available?

Dr. Tanzi: I just did a new album with Joe Perry of Aerosmith and other musicians, including Ringo Starr's son Zak Starkey and Iggy Pop. As you might know, I do keyboards on the side. That album should be coming out next year sometime. I have a music Web site where all my own original music can be streamed for free (https://www.numberonemusic.com/rudytanzi). It has all my music I write, including my album of piano solos, tracking a couple with Alzheimer's disease from first discovery they have the disease to the very end. It has my jazz pieces, a lot of my ambient electronic pieces.

I have an app called Spark Memories Radio. You download it, and you can try it for free for a while. You plug in the age of the patient, and then it plays songs that were hits from when the patient was 13–25 years old because that is the music that emotionally stimulates you and can waken up parts of the brain. The music memory parts of the brain are not affected in Alzheimer's disease, even into late stages. They have circuits going to the short-term memory areas that are affected, so music has a way to spark memories. However, the music has to be music that most emotionally stimulates the person. For most of us, that music is the music we loved when we were between 13 and 25 years old. The person can select whether they like it or whether or it is working, and the algorithm learns the best playlist for each patient.

For nursing homes, we provide special programs where they can have one or two of these on an iPod or phone, or have different patients in the same phone or iPad. All they need to do is pull up that patient's name, and it plays their playlist. We have to pay for the music, so we have got to charge for it, for now.  ■

To Contact Dr. Rudolph Tanzi

Rudolph Tanzi, PhD

E-mail: tanzi@helix.mgh.harvard.edu