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Practical Brain Science

Transcript of Building the Super Brain: Unleashing the Explosive Power of Your Brain

with Ruth Buczynski, PhDand Rudolph Tanzi, PhD

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Building the Super Brain: Unleashing the Explosive Power of Your Brain 2

The National Institute for the Clinical Application of Behavioral Medicinewww.nicabm.com

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Building the Super Brain: Unleashing the Explosive Power of Your Brain

ContentsDefining the “Super Brain” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

The Four Point Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

The Heroes of the Super Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

You Are “Not” Your Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

The Distinction between the Mind and the Brain . . . . . . . . . . . . . . . . . . . . . . 10

Consciousness vs . the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

The Brain as a Tool of Consciousness and Why That Matters . . . . . . . . . . . . . 12

Alzheimer’s Disease: The Early Research . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Important Clues from Early Onset Alzheimer’s Disease . . . . . . . . . . . . . . . . . . 15

Factors that Might Accelerate the Onset of Alzheimer’s Disease . . . . . . . . . . . 18

The Impact of Lifestyle on Developing Alzheimer’s Disease . . . . . . . . . . . . . . 20

About the Speaker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24



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Dr. Buczynski: Hello everyone and welcome back. I’m Dr. Ruth Buczynski, a licensed Psychologist in the State of Connecticut and the President of the National Institute for the Clinical Application of Behavioral Medicine.

My guest is Dr. Rudy Tanzi. He co-discovered several of the Alzheimer’s genes, including the first one, which was the amyloid precursor protein, or APP.

He’s a professor of neurology at Harvard and the director of the genetics and aging unit at Mass General Hospital in Boston.

He’s the author of several books: Decoding Darkness which was written many years ago and then Super Brain.

We’ll get into more about this book, but we’ll also be talking about Alzheimer’s disease, too, because I know that is getting to be more and more important.

So, Rudy, thanks for being here – and welcome!

Dr. Tanzi: It’s a pleasure to be here. Thanks for having me – it’s great.

Defining the “Super Brain”

Dr. Buczynski: I would like to get started with the whole concept of going beyond the baseline brain. Maybe I’ll start by saying what does a “super brain” look like and how would you contrast it with a “regular brain” or a “baseline brain?”

Dr. Tanzi: This idea of super brain – and it was for lack of a better term that we used “super brain” – but I would look at a super brain as being a more mindful, more conscious version of the brain.

In essence, the book is kind of a user’s manual for the brain.

The main idea is that your brain is bringing you sensations, images, feelings, and thoughts – it’s delivering your world to you.

It’s interpreting your world, delivering your world, and producing your world for you. But most of us just basically go along for the ride.

The brain is like a ship with the mind and all of consciousness being like the sea – either you can just be on autopilot and go where the ship takes you, or you can take control and actually steer that ship where you want to go.

Your brain brings you your world – so make it a good one.

Building the Super Brain: Unleashing the Explosive Power of Your Brain

with Ruth Buczynski, PhD and Rudolph Tanzi, PhD

“Your brain is bringing you sensations, images, feelings, and thoughts

- it’s delivering your world to you.”



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That is the basic idea: consciously taking – and I don’t want to say “control” because it’s not about control.

But once you observe what’s going on in your brain in a mindful way, you will induce more connectivity between brain regions, more integration, and this generally will make the brain work at a higher level.

That is the basic concept of a super brain versus a default baseline brain: it is an active consciousness rather than passively letting your brain do what it wants and going along for the ride.

The Four Part Interaction

Dr. Buczynski: We’re going to get into all of what that might involve to achieve as we go along, but you talk about a four-part interaction that we have with our brain that is always taking place. Can you share with us the four parts?

Dr. Tanzi: We like to use, Dan Siegel’s wonderful “handy brain” model based on the triune brain and that is based on the evolution of the brain.

As Dan Siegel explains it, you hold your hand up and bring your thumb in and make a fist – so this would be basically your hind brain, the reptilian brain – the old four hundred million-year-old brain that started with reptiles.

Then you open up and go down to your spinal cord – in the middle we have your limbic brain or your emotional brain. It’s about three hundred million years old.

The newest part of the brain up here is the frontal cortex – the middle two fingers – the prefrontal cortex. This is only four million years old.

These three brain regions basically evolved over hundreds of millions of years, and the basic idea is that you have your reptilian brain driving your instinctive needs: fight or flight, feed, reproduce, stay alive – keep the species going.

Then, you have the limbic system, the emotional brain, where you have fears, desires that in many ways are serving those instinctive cravings and allowing you to be more creative about how you serve those needs.

Finally, you have the intellectual brain, the newest part where you have meaning, purpose in life, creativity, imagination.

So many times, people are living in just one of these areas of the brain: the reptilian, the emotional, or the intellectual.

Perhaps an addict might be just stuck in that reptilian brain, instinctively craving one thing – gambling or drugs or whatever.

“The brain is like a ship with the mind and all of consciousness being like the sea. A super brain is an active consciousness rather than passively letting your brain do what it wants and going along for the ride.”



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You might have someone who’s stuck in the emotional brain – they only feel alive when there’s lots of drama going on, good or bad.

Then I know a lot of people…who just live in that intellectual brain – the old Mr. Spock: “It’s only about logic and reason; emotion doesn’t serve us to stay intellectual.”

We argue in Super Brain that it’s all about connectivity – it’s about integration. You want these three regions of the brain to be talking to each other.

The way you do that is very simple: as soon as you observe what’s going on in your brain, be more mindful of the sensations and images. Be especially mindful of emotions, feelings, and thoughts.

Be more mindful of that internal dialogue when it occurs in your brain. Just by observing it with your frontal cortex, your newest part of your brain, observing what is going on in these other parts of the brain, you’re inducing that connectivity and integration that creates more balance.

What comes out of this is the fourth part of the brain. The fourth main state of mind, I would say, is intuition. Intuition blooms when these three regions of the brain are integrated and connected at the highest level.

Dr. Buczynski: All right, so you ended with intuition and you started with the reptilian brain and the brain stem, the spinal cortex and the frontal lobe and so forth. Let’s go back and just list them…

Dr. Tanzi: We start with the reptilian brain, the hind brain, down to the brain stem. This is the oldest part of the brain – cravings, instinctive needs, survival needs. You’re nowhere without them.

Then you have the limbic brain, and that is your hippocampus and your amygdala. Hippocampus is Latin for “sea horse,” so you have the two “seas” together like this.

In here you have short-term memory and emotion – and as you know, emotion is probably the best thing that can hardwire memory.

We remember where we were on 9/11, every detail. You remember when your first child was born in detail and your second child, too.

Then you have the frontal cortex: longer-term memories, but more importantly, you have reason, judgment, meaning and purpose in life, creativity, and imagination. This area of the brain is only four million years old – it’s the newest part of the brain.

“So many times, people are living in just one area of the brain: the reptilian, the emotional, or the intellectual. We argue in Super Brain that it’s all about connectivity. You want these three regions of the brain to be talking to each other.”

“Just by observing with your frontal cortex, you’re inducing connectivity and integration that creates more balance. Intuition blooms when these three regions of the brain are integrated and connected at the highest level.”

“Emotion is probably the best thing that can hardwire memory.”



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“You can feel sad but know you feel sad, and this is a miracle of the brain. The ‘real you’ is that self-aware being that’s able to observe the sensations, images, feelings, and thoughts that the brain is bringing to you.”

“An infant is totally open to the world, even up to being a toddler.”

What we really stress in Super Brain is self-awareness: don’t take for granted that, even when you’re very, very sad – something bad happens in life and you’re very, very sad – in a split second you can snap out of being sad.

You can actually still feel sad but know you feel sad, and this really is a miracle of the brain. You can be aware of having a certain feeling. You can step back and be aware of having certain thoughts or internal dialog going through your head.

We argue that the “real you,” so to speak, the true you, is that self-aware being that’s able to observe the sensations, images, feelings, and thoughts that the brain is bringing to you.

Once you start to observe these, from this “mountaintop view,” as we like to think about it, as a self-aware person, now you’re allowing these regions to integrate.

You are not mired within them – you are looking from the mountain down into those valleys, allowing them to connect together in one big picture.

The Heroes of the Super Brain

Dr. Buczynski: Now, you describe the “heroes of the super brain” in your book and each one relates to a different brain ideal. Can we go through those?

Dr. Tanzi: Sure. We talk about Einstein as someone who has the ability to adapt, be flexible, and not too rigid in thought – to think outside the box and be creative.

Along the same lines comes a similar idea – a “hero being,” a newborn baby, an infant.

An infant is totally open to the world, even up to being a toddler. The world is just so cool. Every moment is a “Wow!” moment.

My wife and I were late-life parents. We now have a four-year-old girl, and she is just thrilled about every moment of life. She’s learning so well, memorizing a five hundred-word book just like that because emotion hardwires those memories.

When you learn with passion and you’re present in the moment while you’re learning, you learn much better.

What happens as we get older, we’re distracted; we’re jaded; we get apathetic. Instead of “Wow!” moments, we have these “So what?” moments. We start to lose that in-the-moment “Wow!” factor that really promotes learning and memory in the brain.

Then finally, we talk about the Buddha because the Buddha represents more of that conscious brain, more of the mindfulness aspect.



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Again, the book is not intended at all to be religious; we don’t take a stand on any of the religions – in fact we try to mention different religions here and there.

But we do, in particular, talk about the idea of mindfulness and consciously being aware of your thoughts and feelings so that you’re not overtaken by them.

One of the points we make is that it’s probably never correct to say, “I am sad” or “I am angry.” Don’t identify with feelings. Feelings are brought

to you by the brain. The brain is an organ serving the real you, the self-aware you.

We would argue that if you see a red car driving down the street, your brain brings you the image of a red car.

Remote photons are hitting your receptors in your eyes, delivering you this color red, which is specific for our perception. We see a car, and we say, “I see a red car.” You wouldn’t say, “I am a red car.”

But then somebody upsets you and your brain responds to make you feel angry and you readily say, “I’m angry.”

We would say that “I’m angry” is just as foolish as saying, “I’m a red car.”

If you take what mindfulness would tell you – from the Buddha aspect of these heroes – your brain would say, “I observe the fact that I feel angry right now. It’s important to know that’s happening. I’m going to learn from it – but then I’m going to detach and move on. I’m not going to be angry.”

That’s creating limiting belief systems – that’s going to hold you back to identify with a negative emotion. The same thing with being happy – rather than identifying with emotion, the emotion is serving you.

Take that mountaintop view: observe the emotion, use it, learn from it, and move on.

You Are “Not” Your Brain

Dr. Buczynski: This brings me to a couple of things that I’ve heard – first, we get in the way of this process by over-identifying and second, by adapting…where we adapt to things, we get into this “So what?” kind of thinking…We no longer have that wonder that your daughter has at four years old.

How can we overcome the obstacles? You talked about mindfulness as one way to overcome it – and I guess you’ve also talked about seeing the big picture rather than over-identifying with any one thing.

Often we over-identify with our feelings if we’re in the moment of a feeling, or sometimes we over-identify with our perceptions and get attached to our perception of how “the truth went down.”

Dr. Tanzi: Yes. We’d argue to not only not over-identify, but don’t identify at all!

“As we get older, instead of

‘Wow!’ moments, we have these

‘So what?’ moments.”

“We talk about the idea of mindfulness and consciously being aware of your thoughts and feelings so that you’re not overtaken by them.”

“Take that mountaintop view: observe the emotion, use it, learn from it, and move on.”



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“‘What is my brain bringing me?’ and ‘How do I deal with it?’ is the gift we have of self-awareness.”

“The main concept is that you are not your brain. You can be conscious of feelings and thoughts that your brain is bringing you, and rather than identifying with them, we can observe them.”

The main concept of the book is that you are not your brain; you’re not simply the sum of your feelings and thoughts.

Your brain is an organ that is serving you – your brain has self-awareness. Yes, self-awareness is brought to you by these newer parts of the brain – the frontal cortex – but we want to celebrate that and celebrate this gift of self-awareness.

You can be conscious of feelings and thoughts that your brain is bringing you, and rather than identifying with them, we can observe them.

The magic of observing feelings and thoughts, or even observing a craving, observing the fact that right now you want to eat even though you’re not hungry, and realizing it’s just because you’re stressed – you don’t really need the food – means you’re bringing in body awareness.

Observing some type of loop of internal dialog that won’t go away and holding you back – that’s mental mindfulness and mental awareness.

It’s about observing the feelings. For example, you’re upset this morning; you had a bad dream, and you feel bad all day. You can just say, “What am I feeling right now?”

Using that self-awareness to ask, “What is my brain bringing me?” and then saying, “Now, how do I deal with it?” is the gift we have of self-awareness.

It goes on and on. We have body awareness – just paying attention to how you’re breathing at any given moment is important.

Here’s the trick I do – you asked how to do it – and I have a very simple trick. I, like many others, am constantly checking my cell phone. We’re so connected today – texts, emails, and checking who called.

So I made a rule: every time I take out my cell phone…before I do that, I say to myself, “What am I thinking right now? How am I feeling right now? How am I breathing right now? How does my stomach feel – am I hungry? How does my body feel right now? Do I feel heavy? Do I feel light?”

I go through a checklist – body awareness, mental awareness, and social awareness. “How do I feel about the world right now?”

I go through a quick checklist of, “Where am I at? How do I feel right now? What am I thinking? What am I craving?” – I do this just to be in touch.

I’m doing basically a self-check of this organ, this amazing three-pound organ in my head that brings me my world.

I’m doing this so I can bring myself a better world that I want to live in. My brain produces my whole world. My world wouldn’t be there without my brain.



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“I go through a checklist - body awareness, mental awareness, and social awareness.

‘How do I feel about the world right now?’ My brain produces my whole world. My world wouldn’t be there without my brain.”

Dr. Buczynski: So how long do you spend doing that check-in before you check your cell phone?

Dr. Tanzi: In the beginning, it takes a little bit of time because you don’t have a routine. As you know, the brain is incredibly vulnerable to repetition.

Anything you want the brain to do over and over again, just with persistence and repetition and you know the old adage, “Neurons that fire together wire together” – is retraining pathways.

You’re remodeling this incredible neural network with neuroplasticity all the time. With repetition, you get into more of a routine of how to do it.

The process is different for everybody. Some people need to be more cognizant of how they feel; they might be more emotional.

Some people might need to be more cognizant of when they’re stuck in some intellectual loop. Some people might be more instinctive. So it’s different for each person.

Just take three deep breaths before you do anything with the phone and simply say – we like to say, “Smile, smile inside, and smile with your body” – and then say, “Okay, now how do I feel?” Just by doing that observation, you’re integrating brain areas and the brain will work better.

If you think about the greatest achievements on earth, you think about Galileo and da Vinci and Mozart. They had plenty of reptilian brain; they had plenty of drive – right?

They had plenty of emotion, they had plenty of passion, and they had plenty of frontal cortex creativity, imagination, and looking for meaning and purpose.

It was this integration – the interconnectedness of all three (the reptilian brain, emotion, and frontal cortex creativity) that made them special and able to produce these works of art that have withstood all of history, modern history.

The Distinction between the Mind and the Brain

Dr. Buczynski: I would like to move into the distinction between the mind and the brain. You talk about in your book a study that was done by Wilder Penfield – some of the folks on the call might remember studying that in their general psyche course in college.

“You’re remodeling this incredible neural network with neuroplasticity all the time. With reptition, you get into more of a routine of how to do it.”

“Just take three deep breaths before you do anything with the phone and by doing that observation, you’re integrating brain areas and the brain will work better.”



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This is a study done in the 1930s, and it was trying to show the distinction between the mind and the brain. Can you tell us about what he did?

Dr. Tanzi: Yes, I’m just thinking – trying to remember…it’s been a while…

Dr. Buczynski: I probably know more about your book at this little moment than you do!

Dr. Tanzi: Yes! Could be! Basically what Penfield was doing was stimulating the brain to make someone’s arm move.

This was illustrating the difference between consciously saying, “I’m going to make my arm move,” as opposed to being able to stimulate a part of the brain that automatically makes the arm move.

The difference is that if you tell the subject, “Move your arm,” then the mind is giving a command to the brain that says, “I want to move my arm.” It’s a conscious decision, but if you stimulate the brain to make the arm move automatically, the subject will say, “My arm moved.” He won’t say, “I moved my arm.”

That’s the difference between the brain carrying out its role as an organ to move your arm, versus your mind giving the command to your brain, “I want to move my arm.”

We would argue that mind over brain is the key. Your brain will react to your mind – respond to your mind – every time you want.

If you imagine a sunset right now, your visual cortex gets turned on: neuroplasticity is going on there, gene activity is changing, and your neurochemistry is changing.

Your mind can exact physical changes in the brain – and I think we tend to forget this. We have the power, with our mind, to rewire our neural networks as we wish and that with repetition we can rewire our neural networks to basically enhance (the neural network we want).

The mind is that active part that is basically where the brain is serving the mind.

Our goal is to have people become the users of their brain, where the brain serves the mind.

Basically, Penfield gives us this example where the difference between “I moved my arm” versus “My arm just moved” is the difference between the mind making the command through the brain or the brain doing it automatically.

Consciousness vs. the Brain

Dr. Buczynski: Which comes first – consciousness or the brain?

“Your brain will react to your mind - respond to your mind - every time you want.”

“‘I moved my arm’ versus ‘My arm just moved’ is the difference between the mind making the command through the brain or the brain doing it automatically.”



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“Consciousness precedes the brain.”

Dr. Tanzi: That’s the big debate. My training is in neuroscience at Harvard.

I’m sure that many of my colleagues in the neuroscience neurobiology program, when they read the book or if they see the show we did on the book, (they might not agree) but I’m making the argument with Deepak – I came to agreement with Deepak Chopra – that consciousness precedes the brain.

This is a big statement for a neuroscientist because, of course, the natural reaction – their answer would be to say that there is only consciousness when the brain produces it.

But I guess there are many reasons why I think this. It just makes more sense, and I’ll be very honest: I have gotten to the point now, in thinking about the universe in general, that the fact that your brain is bringing you your whole world is a matter of trust.

When light hits my eyes, my brain brings me the color red. There’s no such thing as “the color red” – it’s a specific construct of my brain.

The color red is the way my brain is interpreting for me energy – the electromagnetic energy and photons coming in – signals going to my brain.

So now, I hit my desk, and I say, “Here’s evidence that the material world exists,” as I hit the desk and I can feel it.

There are receptors in my hand that, again, are bringing electrochemical signals to my brain to make me experience – just like I experienced red – I experience a very human (and other species do too) species-specific

sensation of material which I can hit with my hand.

Most, if not all of us, are physicalists: we believe that there actually is space and there are little physical objects – particles, subatomic particles, larger constructs – floating around in space.

To be honest, after doing this book and really, really giving this a lot of thought, the idea of an actual physical world with physical things floating around in it is like Santa Claus for me. It’s like the Easter bunny. It almost seems childish to need to have that security blanket – to believe there are actual physical objects.

This is all to say, as a prelude – and you’re getting me to admit this – that it’s easier for me to see all of existence as consciousness.

We, as humans, are one example of consciousness becoming aware of itself. So, in this model, the brain itself is part of consciousness. We are part of consciousness. We allow consciousness, in a feedback loop, to become aware of itself.

This is a more metaphysical belief. I’m a scientist, a neurogeneticist and I do microcell biology, microbiology, but this is honestly what I now believe in my heart.

Scientifically, of course, I’ll be dead for centuries before we prove any of this, if it is proven!

But metaphysically, it makes more sense to me that…we have consciousness becoming aware of itself through the construct of the brain. It is complexity of information – density of information – as consciousness becomes aware of itself.



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So, for me, the brain is a tool of consciousness that allows it to be aware of itself. That’s why self-awareness is so important.

The Brain as a Tool of Consciousness and Why That Matters

Dr. Buczynski: If someone were to say, “So what? That’s just an academic argument.” I would imagine you would say, “No – that matters

in many ways.” What are some ways that it matters?

Dr. Tanzi: It matters because if you see the universe more from the standpoint of consciousness and then consciousness has to be aware of everything including itself, you start seeing things more as information.

You start seeing even the human body and the brain as higher-order structures – a complexity of information within consciousness as it becomes aware of itself.

You get away from what I see as a more childish view of physical versus nonphysical – now we can have more of a unified view of the universe.

What’s nice about that is you realize that you have more control about the world you live in. You’re not just a little victim getting pelted by “mental meteorites,” so to speak.

You are part of consciousness and your brain is interpreting the world within consciousness. You have the power to interpret the world any way you want no matter what’s happening outside.

With all the major tragedies we saw last year, these tragedies remind you instead to be more humane, to be kinder, to be more compassionate. They’re reminders that we have to do better.

So rather than identifying with a bad world, you say, “You know what? I see what’s happening in the world. I see what’s happening in that web of consciousness, and internally, here’s how I like to interpret the world and here’s what I need to do about myself in view of what I just experienced and observed from watching these tragic events on TV.”

It allows you to produce the world you want to live in – because, let’s face it, the only world you have is the world your brain brings you. Your brain is bringing you that world by interpreting – I believe – a larger sea of consciousness.

Alzheimer’s Disease: The Early Research

Dr. Buczynski: Let’s move into Alzheimer’s disease. That’s the area that you have specialized in for all these years.

Dr. Tanzi: You’re bringing me back to being a scientist – thank you.

“You have the power to interpret the world any way you want no matter what’s happening outside.”

“We, as humans, are one example of consciousness becoming aware of itself.”

“We have consciousness becoming aware of itself through the construct of the brain. The brain is a tool of consciousness.”



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Dr. Buczynski: Is that more comfortable?

Dr. Tanzi: Yes.

Dr. Buczynski: What got you into studying Alzheimer’s disease?

Dr. Tanzi: Way back when I was an undergrad, it was the early days of recombinant DNA and I just thought gene splicing was so cool. It was controversial – I was a kid – and that’s what I wanted to do.

When I started at Mass General Harvard, right out of college, I was very lucky to work with Dr. Jim Gusella (Director: Bullard Professor of Neurogenetics in the Dept. of Genetics Harvard Medical School and Center for Human Genetic Research, Massachusetts General Hospital) – and at the time I was twenty-two.

Jim Gusella was maybe twenty-seven, and he had this idea that you could find a disease gene using genetics, which was absurd at the time, and he had the idea that you could find variations in DNA – DNA markers, so to speak – to track down a disease. A gene for a disease, where we knew nothing about the disease, was Huntington’s.

This project started in 1980, and it was Jim Gusella’s idea. I was the hands at the bench doing the work with him. He was also my PhD advisor.

We got really lucky in just testing a handful of the very first variations in the genome – now we call them SNPs, single nucleotide polymorphisms…but just testing a handful of them, we hit the Huntington’s gene.

In fact, now when we look back at what we did, the odds against that were twenty thousand to one in terms of how many genetic markers we looked at and how fast we hit it.

Also, I basically had to think about my thesis work, and the idea was I was going to build the first full map of a chromosome, the genetic map of a chromosome with genetic markers spanning one end to the other.

I picked chromosome 21 because it was the smallest and I wanted to get it done quickly – that’s what students do.

Once I started building this map of 21, I was just a kid but I became the “chromosome 21 go-to guy.” This was pre-Human Genome Project; this was when every chromosome had its person; it was all “Mom and Pop” stuff, and I became the chromosome 21 genetic map person.

People would call me and say, “I need to map this gene. Can you tell me where it is and can I use your map?”

Then along the way, I was able to study Down’s syndrome, because of course in Down’s syndrome, you have three copies of chromosome 21 and you have this whole constellation of

symptoms.

“The only world you have is the world your brain brings to you.”

“When we look back at what we did, the odds against that were twenty thousand to one in terms of how many genetic markers we looked at and how fast we hit it.”



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What really got my interest was an article in News and Views in Science by Jean-Maurice (Delabar) that talked about Down syndrome and how, inevitably by middle age, the pathology of Alzheimer’s arises in terms of the senile plaques and tangles.

I said, “Wow! That means that I might have the map right here to find the first Alzheimer’s gene.”

Basically, the speculation was that there would be an Alzheimer’s gene like chromosome 21 because why else would Down syndrome patients, who have three copies of 21, suffer from Alzheimer’s pathology later on in life?

Working off that hunch, I decided to look for the gene that creates the amyloid, the beta-amyloid and the senile plaques.

This was a lot of hunch, a lot of guessing, a lot of speculation – and to be honest, in my program at Harvard, many of my elders and supervisors were telling me I was wasting my time – this was a red herring, and I was just a kid. But the more I heard that, the more I wanted to do it. Actually, it all turned out well. I ended up finding the APP, the amyloid precursor protein gene that gives rise to the amyloid that is in chromosome 21. All the speculation worked out.

Then once I “co-discovered” the first gene – it’s never a one-person job – I got into Alzheimer’s. I never looked back, and I’ve been looking for Alzheimer’s genes even to this day.

I direct the Cure Alzheimer’s Fund, the Alzheimer’s genome project, which is now a ten million-dollar new project doing whole-genome sequencing on 1500 subjects from Alzheimer’s families to find all of the DNA variations that lead to this disease.

It’s probably one of the biggest whole-human-genome sequencing projects in any disease today – and we’re just getting going. It’s a lot of fun.

Dr. Buczynski: What did you actually have to do to prove that that was the Alzheimer’s gene?

Dr. Tanzi: At that time, we had these families with early onset familial Alzheimer’s disease.

Dr. Buczynski: What age would that be – forty, fifty?

Dr. Tanzi: It was under sixty, but actually the average age of onset was between forty and fifty.

We had several of these families, and what we found was that, even before finding the amyloid gene, we found that there were markers on my chromosome 21 map that were linking to Alzheimer’s disease in some of these families.

“I ended up finding the APP, the amyloid precursor protein gene that gives rise to the amyloid that is in chromosome 21.”

“What really got my interest was an article about Down syndrome and how the pathology of Alzheimer’s arises in terms of the senile plaques and tangles.”



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“All of those genes together paint a pretty clear picture of what is happening in the disease in terms of familial early onset and instructing us about Alzheimer’s in general.”

“We found markers on my chromosome 21 map that were linking to Alzheimer’s disease in some of these families.”

Then, we basically looked for linkage of the amyloid gene itself to Alzheimer’s.

Ultimately, a few years later, as the amyloid gene became the one and only top candidate gene for Alzheimer’s, the genetic linkage looked good.

Folks in Britain were able to find the first mutation in that gene. I had to wait a couple of years before the gene was totally validated by finding the first mutation in it that causes familial early onset Alzheimer’s. That became known as the “London mutation.”

But now we know there are about thirty or so mutations in the amyloid gene. We can also have duplications of that gene causing the disease – akin to what happens in Down syndrome.

Most of the early onset Alzheimer’s, familiar Alzheimer’s, involves two other genes that, again, we co-discovered, called the presenilins – presenilin 1 and presenilin 2 – and most of the mutations we know about are in presenilin 1, but a handful are in presenilin 2.

All of those genes together paint a pretty clear picture now of what is happening in the disease in terms of familial early onset and instructing us about Alzheimer’s in general.

Important Clues from Early Onset Alzheimer’s Disease

Dr. Buczynski: I wanted to mention, too, a little bit about Alzheimer’s in general. Have you been studying – and it’s terribly tragic…Alzheimer’s in general or mostly just focusing on early Alzheimer’s?

Dr. Tanzi: To be honest, the early onset Alzheimer’s genes really gave us so many clues about what’s going on. When we looked at the APP gene and the presenilins, we noticed what they have in common.

When you had mutations in these genes – and I should say there are about two hundred mutations in presenilin 1, a handful in presenilin 2, and about thirty in APP – and together, those three genes account for maybe one or two percent of all Alzheimer’s disease that strikes early.

Even in the early onset cases, we know there are other genes involved and we are just finding some of those now.

But those three genes taught us something. They all have one thing in common: the mutations, or at least most of them, increased the ratio of a long form of the amyloid beta protein versus a short form.

If we back up, the plaques in Alzheimer’s are made up of the amyloid beta protein; the first gene we found was the precursor for that or amyloid precursor protein.



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If you have mutations in the APP, like the London mutation – the amyloid beta protein that was made – you have a little bit more of it with two extra amino acids on one side, so it is a longer form.

We call that A beta 42. Usually A beta 42 is about ten percent of the pool of A beta in the brain; the other ninety percent, or most of it, is A beta 40.

So when the long form (A beta 42) to the short form (A beta 40) ratio goes up, you drive more amyloid accumulation in the brain.

We found that the mutations in APP did that, and then low and behold, the mutations in these new genes, the presenilins, in ‘95, did the same thing. We showed that in ‘96 with others.

So here’s the bottom line – the way it all turned out, and I’ll grab a pen to illustrate this. If you take this pen, this is what APP would look like, and that little gold band in the middle would be the amyloid beta protein.

We learned that we have to clip at enzymes to get that out and released from the brain. The presenilins clip that other side where you can really get the long form or short form.

This was a revelation because it said that all of the early onset genes have one thing in common: totally different genes, different proteins – but the mutations led to the same end –

increased ratio of A beta 42 to 40, leading to more amyloid in the brain.

More amyloid in the brain triggers the tangle pathology and neurons die. That triggers inflammation and you go down that slippery slope to Alzheimer’s.

If you want to nip the disease in the bud, you curb the accumulation of amyloid over one’s lifetime. That is what those genes taught us.

In fact, now I have drugs that are being developed – company-free – where the NIH is acting as our pharmaceutical partner, so to speak, so there are no strings attached.

The NIH is developing these drugs called gamma-secretase modulators with us.

They’re being developed by colleague Steve Wagner at UCSD, and again, the NIH acts like our pharma-partner: they help make the drugs, and they help do the structure activity relationships – all the medicinal chemistry. So we’re very excited.

What these drugs do is simply say, “If we know that when the ratio of A beta 42 to 40 goes up, you can get Alzheimer’s disease as early as twenty years old in some of our families, so let’s just turn the ratio the other way. Let’s find compounds that make the ratio go the other way – bring 42 down and 40 up.”

“The mutations increased the ratio of a long form of the amyloid beta protein versus a short form. When the long form (A beta 42) to the short form (A beta 40) ratio goes up, you drive more amyloid accumulation in the brain.”

“If you want to nip the disease in the bud, you curb the accumulation of amyloids over one’s lifetime. That is what those genes taught us.”

“The NIH is developing these drugs called gamma-secretase modulators with us.”



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That was the idea that Steve Wagner and I had, and now we have these compounds that have been in development now for ten or fifteen years.

But that all was made possible by these rare mutations that caused early onset Alzheimer’s, and that’s what taught us how to do it.

Dr. Buczynski: In your book, it was hard to believe that brains affected by Alzheimer’s can be reduced to two pounds or less.

Dr. Tanzi: Yes, and this is what happens. If you look at the pathology there with the plaques, most of the evidence says that in response to the amyloids, certain neurons are vulnerable, and they make the tangles which are made of the protein tau.

These neurons start dying, the tangles get released, and they spread. A tangle can go to a healthy neuron and make a tangle there. Eventually, there’s neuronal cell death.

Initially, the glial cells try to keep up: they try to clear away the amyloid, clear away the neuronal debris of dying neurons, and clear away the degenerating synapses and neurites.

But eventually they throw up their hands and say, “Look, we can’t keep up.” At this point, the glial cells go into that other state where they become detrimental.

They start shooting off free radicals, cytokines, as inflammation. With that amount of neuronal cell death, you get the inflammation or “friendly fire” – it’s probably worse than what you get from the plaques and tangles alone.

At that point, as you’re losing more and more neurons and more and more synapses, the brain begins to shrink.

We start to see atrophy and you can stick almost your whole finger into a gyrus or a sulcus, whereas before, it was pretty much flesh – so that atrophy takes its toll.

The picture of an Alzheimer’s brain versus a healthy brain is remarkable.

Factors that Might Accelerate the Onset of Alzheimer’s Disease

Dr. Buczynski: Let’s talk about average onset – later onset of Alzheimer’s disease. What are some of the environmental or external factors that might accelerate it?

Dr. Tanzi: Even in the late onset forms of Alzheimer’s, if you look at twin studies, at least eighty percent of Alzheimer’s involves inherited factors.

I would say, at the end of the day, it would be tough to find a case of Alzheimer’s that doesn’t involve some genetic interaction – some genetic susceptibility.

“‘Let’s find compounds that make the ratio go the other way - bring 42 down and 40 up.’”

“In response to the amyloids, certain neurons are vulnerable, and they make the tangles.”

“The picture of an Alzheimer’s brain versus a healthy brain is remarkable.”



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“It would be tough to find a case of Alzheimer’s that doesn’t involve some genetic interaction - some genetic susceptibility.”

I’d suspect that the earlier the age of onset, the more robust the genetics. You have these rare mutations of the ones in APP and the presenilins – those rare mutations guarantee onset. They’re a hundred percent penetrant – there’s nothing you can do to stop it.

As you get into the late onset disease, you have the gene ApoE or apolipoprotein E, where it acts as a risk factor.

Inheriting the epsilon 4 variant of ApoE increases your risk by about three or fourfold if you have one copy. If both parents give you a copy, it is over tenfold.

But unlike those early onset mutations, the ApoE 4 variant doesn’t guarantee the disease.

For a long time, those were our only four genes we knew, and then at the beginning of this century, our lab – when we did the Alzheimer’s genome project with the Cure Alzheimer’s Fund – other consortia got going.

We said, “Now we have the databases; we have the chips; we have enough variants in the genome. We can screen a million variants at a time and find the other genes.”

I think back and I say, “Wow, back with Jim Gusella in 1980, we tested the first five SNPs ever in a genome” – we thought we had to pull them out.

Today, I say, “Here I’m doing the same thing thirty years later, but now I’m doing it with chips and a million variants at a time. We’re doing whole genome sequencing, and we’re going to find thirty million variants at a time.”

It’s all about finding these variants that teach you what’s going on.

In most cases with late onset Alzheimer’s, it’s the interplay of genetic variants that affect your susceptibility – some increasing risk in conferring protection – we found about a fifty/fifty split – and then there’s the issue of how you live your life.

I would say that the biggest, most useful information that came out of these whole genome screens over the past few years is in the unbiased manner we find the new genes and say, “Wow – how does that gene

cause Alzheimer’s disease? How could that gene be involved?”

Lots of times you get the gene name after you follow the DNA markings and say, “Here’s where the gene is,” and then say, “What the heck is that?”

There are some patterns that are emerging now. In 2008, we reported a new Alzheimer’s gene called CD33.

CD33 is involved with the brain’s immune system, and I’ll just fast-forward here. We figured out that CD33 is controlling whether the

“But unlike those early onset mutations, the ApoE 4 variant doen’t guarentee the disease.”

“With late onset of Alzheimer’s, it’s the interplay of genetic variants that affect your suceptibility.”



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immune system of the brain stays beneficial – meaning the glial cells are clearing away the amyloid, clearing away the debris, and saying, “There’s something wrong here.”

The glial cells are shooting out neural-protective extrinsic factors, as opposed to the glial cells throwing up their hands and going militaristic and saying, “You know what? With this much damage in the brain, there must be an infection. We want to shoot out cytokines and free radicals.”

This reaction gives us the “Don Quixote effect” where the glial cells are shooting at windmills, but they are killing neurons in the process.

So the big question is: what genes control which glial cells stay beneficial, help clear up the mess and protect neurons, or throw up their hands and cause more damage than they do good – causing more neuronal cell death than the original plaques and tangles?

CD33, and now more recently this other gene, TREM2, are in this pathway, and this is really amazing because it says that for the first time we can think about targeting those genes – or more specifically the proteins made by those genes – with drug discovery that will modulate your brain’s immune system to keep it beneficial but not go into that very detrimental inflammatory state that really takes out the brain.

Dr. Buczynski: Is it all going to come down to genes and drugs?

Dr. Tanzi: In some cases, you need drugs. I hope that someday we’ll have a world where our lifestyle – we know enough about how to live our lives and how to use our minds and brains, will be such that we can avoid the need for drugs.

But then you look at these cases with these fully penetrant mutations and APP that guarantee disease by forty, or some of the presenilin mutations that guarantee disease by twenty, and lifestyle is not probably going to do a whole lot there. You’re probably going to need a pretty good yogi to meditate your way out of that disease.

The Impact of Lifestyle on Developing Alzheimer’s Disease

Dr. Buczynski: How about when you’re in your eighties? Does lifestyle have more of an impact on whether you develop Alzheimer’s disease at that age?

Dr. Tanzi: Yes, yes. For those rare cases that occur very early, you may need drugs.

But my hope would be for the later onset cases – seventies, eighties, nineties – we’ll understand enough about the interaction between gene variants and lifestyle that we can adapt the lifestyle to overcome those genetic susceptibilities and not need the drugs. I believe that’s going to happen one day.

Dr. Buczynski: What are you predicting? What directions look most fruitful in terms of lifestyle?

“We figured out that CD33 is controlling whether the immune system of the brain stays beneficial. The big question is: what genes control which glial cells stay beneficial.”



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“‘What is good for the heart is good for the brain.’ In getting physical exercise, you induce new genetic activity that makes the enzymes and peptidases to clear amyloid from the brain.”

Dr. Tanzi: Right now, in terms of lifestyle, the rule is still, “What is good for the heart is good for the brain.” So, physical exercise is number one.

Physical exercise induces neurogenesis in the hippocampus, which means that you make neural stem cells in the hippocampus with exercise.

A colleague of mine, Sam Sisodia, has shown that physical exercise is as a good as any drug tried in an Alzheimer’s mouse model for clearing the amyloid.

In getting physical exercise, you actually induce new genetic activity that makes the enzymes and peptidases to clear amyloid from the brain – it’s amazing.

Diet: a high-fat or high-carb diet is not good for your heart and it’s not good for your brain. If you induce your risk for neurovascular events and stroke, you’re inducing insults – maybe even unnoticed – TIAs in the brain that are going to drive some of this pathology like plaques and tangles. So, good diet is important.

More recently, along the idea of social connectedness, loneliness has been found as a risk factor for Alzheimer’s.

Loneliness, together with depression – as opposed to staying socially connected and socially engaged – the brain is happy when you do that. The epidemiology says that loneliness is a risk factor.

Again, it’s physical exercise, social engagement, good diet – and the last one is what we’re doing right now: intellectual stimulation.

As people are being stimulated by this discussion, they are protecting themselves from Alzheimer’s because they are making the synapses.

All learning, as you know, is by association. When you make new synapses, you strengthen the ones you already have – it’s like money in bank.

What correlates with the degree of dementia in Alzheimer’s? Number one is loss of synapses. It’s no the numbers of plaques or tangles or anything else – it’s the loss of synapses that correlates with the degree of dementia.

The more synapses you make and the more you strengthen them, then the more you can lose before you “lose it.”

Those would be the “big four.”

Dr. Buczynski: I know we had a speaker at our conference in Hilton Head who was an epidemiologist and studying loneliness, and he talked about loneliness.

“Loneliness has been found as a risk factor for Alzheimer’s. ”

“It’s physical exercise, social engagement, good diet - and the last one is what we’re doing right now: intellectual stimulation. ”

“The loss of synapses correlates with the degree of dementia.”



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If you just take a population of people who have been diagnosed with Alzheimer’s disease some time in their eighties, those who have less social contact are going to get the disease – it’s going to develop more quickly in them.

For those who have more social contact, they might be carrying the disease, but it’s going to manifest itself less in what it’s done to their personality.

Dr. Tanzi: Yes, there have been plenty of studies to confirm this – the social connectedness and often, along with that, the stimulation.

If you’re connected socially, you’re learning new things just when you’re with somebody. You’re getting that new synaptic activity.

I think the key is to keep moving: keep moving physically, keep moving mentally, and keep moving spiritually. It’s mindfulness of mind over brain – inducing connectivity between brain regions – just all of this novelty.

What does it do? You’re making new synapses; you’re causing neuroplasticity. If you’re exercising, you’re even causing neurogenesis – you’re rejuvenating the brain; you’re not letting it stagnate.

Just blood flow alone – a good brisk walk and exercising! I think about the brain like a town or a city: you can think about London when the sewers were just stagnating out in the streets. It was an old city – and then it was rejuvenated.

You need to think of the brain in the same way. You need to keep blood flow going in the brain; you need glucose being delivered to neurons.

Synaptic activity is one and the same with glucose utilization. So, it’s all about staying engaged. It’s staying stimulated physically, mentally – and we would argue – spiritually. That connectivity of the brain – integration of the brain – is very important.

Dr. Buczynski: That is a good note to end on. What I just heard you say is that it’s important to keep moving: moving mentally, physically and spiritually.

I think people, our patients, may be more logically connected to the “physically” and the “mentally” part, but the “spiritually” part…does integrating the spiritual part help us integrate the brain more? Did I get that right?

Dr. Tanzi: Yes. It’s the idea of spiritual mindfulness – the idea that you are being mindful of your thoughts and feelings rather than identifying with them.

Taking the mountaintop view of them allows your frontal cortex to create connectivity or strengthen connectivity with the older reptilian and limbic parts of the brain.

“The key is to keep moving: keep moving physically, keep moving mentally, and keep moving spiritually.”

“You need to keep the blood flow going in the brain; you need glucose being delivered to neurons. ”



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We want to have these brain areas integrated – and a lot of this thinking comes from Dan Siegel’s work – the idea of interpersonal neurobiology, which I really subscribe to, and the idea that a connected brain, an integrated brain, is a healthier brain. That is where we talk about spiritual exercise, so to speak.

Dr. Buczynski: Thank you so much. I very much appreciate the work that you have done.

My guest today has been Rudy Tanzi. He is at Harvard, a professor of neurology, and he was the first co-discoverer of the first Alzheimer’s gene and has since discovered many, many more.

I am excited to see where you’ll be going next – what you’re going to do and what the field is going to do as we are all coping with Alzheimer’s disease.

It is taking such a toll on families and on lives, precious lives. It just has such an impact on us.

So thank you for your work – and I’m excited to hear more about what you do and where you take that.

Thanks very much to everyone – thanks for being here. And, Rudy, especially to you, thanks for being here.

Dr. Tanzi: Thanks for having me. I really enjoyed our discussion.



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About The Speaker:

Dr. Rudolph Tanzi is a Professor of Neurology and holder of the Joseph P. and Rose F. Kennedy Endowed Chair in Neurology and Mental Retardation at Harvard University. At the Massachusetts General Hospital (MGH), Dr. Tanzi serves as the Director of the Genetics and Aging Research Unit. He has investigated the molecular and genetic basis of neurological disease and the genetic causes of Alzheimer’s disease (AD).

Dr. Tanzi currently spearheads the Alzheimer’s Genome Project, which recently identified four new AD gene candidates. He has co-authored over 340 research articles. and is also a co-author of a popular trade book on Alzheimer’s disease entitled Decoding Darkness: The Search for the Genetic Causes of Alzheimer’s Disease.

Find out more about this and related programs at: www.nicabm.com

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