0:00:01.117,0:00:06.342
How many people here would like to live[br]to be at least 80 years old?

0:00:06.342,0:00:07.956
Yeah.

0:00:07.956,0:00:10.618
I think we all have[br]this hopeful expectation

0:00:10.618,0:00:12.828
of living into old age.

0:00:12.828,0:00:15.135
Let's project out into the future,

0:00:15.135,0:00:16.718
to your future yous,

0:00:16.718,0:00:19.595
and let's imagine that we're all 85.

0:00:19.595,0:00:22.851
Now everyone look at two people.

0:00:22.851,0:00:27.130
One of you probably has[br]Alzheimer's disease.

0:00:30.813,0:00:32.666
Alright, alright.

0:00:32.666,0:00:35.190
And maybe you're thinking, well,

0:00:35.190,0:00:37.565
it won't be me.

0:00:37.565,0:00:41.370
Then, okay, you are a caregiver.

0:00:45.472,0:00:47.035
So in some way,

0:00:47.035,0:00:50.933
this terrifying disease[br]is likely to affect us all.

0:00:50.933,0:00:53.971
Part of the fear around Alzheimer's[br]stems from the sense

0:00:53.971,0:00:56.409
that there's nothing we can do about it.

0:00:56.409,0:01:01.558
Despite decades of research, we still[br]have no disease-modifying treatment

0:01:01.558,0:01:03.401
and no cure.

0:01:03.401,0:01:05.814
So if we're lucky enough[br]to live long enough,

0:01:05.814,0:01:09.544
Alzheimer's appears to be[br]our brain's destiny.

0:01:09.544,0:01:11.649
But maybe it doesn't have to be.

0:01:11.649,0:01:15.375
What if I told you we could[br]change these statistics,

0:01:15.375,0:01:17.688
literally change our brain's destiny,

0:01:17.688,0:01:22.118
without relying on a cure[br]or advancements in medicine?

0:01:22.118,0:01:24.579
Let's begin by looking at[br]what we currently understand

0:01:24.579,0:01:27.486
about the neuroscience of Alzheimer's.

0:01:27.486,0:01:30.763
Here's a picture[br]of two neurons connecting.

0:01:30.763,0:01:34.144
The point of connection,[br]this space circled in red,

0:01:34.144,0:01:35.807
is called the synapse.

0:01:35.807,0:01:39.023
The synapse is where[br]neurotransmitters are released.

0:01:39.023,0:01:41.314
This is where signals are transmitted,

0:01:41.314,0:01:43.595
where communication happens.

0:01:43.595,0:01:45.637
This is where we think,

0:01:45.637,0:01:48.445
feel, see, hear, desire,

0:01:48.445,0:01:50.272
and remember.

0:01:50.272,0:01:53.184
And the synapse[br]is where Alzheimer's happens.

0:01:53.184,0:01:55.169
Let's zoom in on the synapse

0:01:55.169,0:01:58.918
and look at a cartoon representation[br]of what's going on.

0:01:58.918,0:02:01.179
During the business[br]of communicating information,

0:02:01.179,0:02:05.063
in addition to releasing neurotransmitters[br]like glutamate into the synapse,

0:02:05.063,0:02:07.649
neurons also release a small peptide

0:02:07.649,0:02:10.190
called amyloid beta.

0:02:10.190,0:02:15.625
Normally, amyloid beta is cleared away[br]and metabolized by microglia,

0:02:15.625,0:02:18.167
the janitor cells of our brains.

0:02:18.167,0:02:22.026
While the molecular causes[br]of Alzheimer's are still debated,

0:02:22.026,0:02:25.566
most neuroscientists believe[br]that the disease begins

0:02:25.566,0:02:28.785
when amyloid beta begins to accumulate.

0:02:28.785,0:02:31.740
Too much is released,[br]or not enough is cleared away,

0:02:31.740,0:02:35.098
and the synapse begins[br]to pile up with amyloid beta.

0:02:35.098,0:02:37.522
And when this happens, it binds to itself,

0:02:37.522,0:02:41.528
forming sticky aggregates[br]called amyloid plaques.

0:02:41.528,0:02:45.184
How many people here[br]are 40 years old or older?

0:02:45.184,0:02:48.311
You're afraid to admit it now.

0:02:48.311,0:02:50.130
This initial step into the disease,

0:02:50.130,0:02:52.977
this presence of amyloid[br]plaques accumulating,

0:02:52.977,0:02:56.430
can already be found in your brains.

0:02:56.430,0:02:58.813
Now, the only way we could[br]be sure of this would be

0:02:58.813,0:03:00.743
through a PET scan, because at this point,

0:03:00.743,0:03:03.605
you are blissfully unaware.

0:03:03.605,0:03:08.049
You're not showing any impairments[br]in memory, language, or cognition

0:03:08.049,0:03:09.471
yet.

0:03:09.471,0:03:14.032
We think it takes at least 15 to 20 years[br]of amyloid plaque accumulation

0:03:14.032,0:03:16.248
before it reaches a tipping point,

0:03:16.248,0:03:18.696
then triggering a molecular cascade

0:03:18.696,0:03:21.810
that causes the clinical[br]symptoms of the disease.

0:03:21.810,0:03:23.688
Prior to the tipping point,

0:03:23.688,0:03:26.608
your lapses in memory[br]might include things like,

0:03:26.608,0:03:29.464
"Why did I come in this room?"

0:03:29.464,0:03:32.192
or "Oh, what's his name?"

0:03:32.192,0:03:35.435
or "Where did I put my keys?"

0:03:35.435,0:03:39.419
Yeah, now before you all[br]start freaking out again,

0:03:39.419,0:03:40.645
because I know half of you

0:03:40.645,0:03:42.978
did at least one of those[br]in the last 24 hours,

0:03:42.978,0:03:46.816
these are all normal kinds of forgetting.

0:03:46.816,0:03:49.153
In fact, I would argue that these examples

0:03:49.153,0:03:51.154
might not even involve your memory,

0:03:51.154,0:03:52.634
because you didn't pay attention

0:03:52.634,0:03:55.611
to where you put your keys[br]in the first place.

0:03:55.611,0:03:57.312
After the tipping point,

0:03:57.312,0:03:59.519
the glitches in memory,[br]language, and cognition are different.

0:03:59.519,0:04:03.612
Instead of eventually finding[br]your keys in your coat pocket,

0:04:03.612,0:04:05.507
or on the table by the door,

0:04:05.507,0:04:08.539
you find them in the refrigerator,

0:04:08.539,0:04:10.366
or you find them and you think,

0:04:10.366,0:04:12.672
"What are these for?"

0:04:12.672,0:04:16.362
Okay, so what happens[br]when amyloid plaques

0:04:16.362,0:04:18.217
accumulate to this tipping point?

0:04:18.217,0:04:21.559
Our microglia janitor cells[br]become hyper-activated,

0:04:21.559,0:04:25.716
releasing chemicals that cause[br]inflammation and cellular damage.

0:04:25.716,0:04:28.196
We think they might actually[br]start clearing away

0:04:28.196,0:04:30.620
the synapses themselves.

0:04:30.620,0:04:33.650
A crucial neural transport protein[br]called tau becomes hyperphosphorylated

0:04:33.650,0:04:37.478
and twists itself[br]into something called tangles

0:04:37.478,0:04:40.443
which choke off the neurons[br]from the inside.

0:04:40.443,0:04:44.179
By mid-stage Alzheimer's,[br]we have massive inflammation and tangles

0:04:44.179,0:04:46.366
and all-out war at the synapse

0:04:46.366,0:04:48.238
and cell death.

0:04:48.238,0:04:51.350
So if you are a scientist[br]trying to cure this disease,

0:04:51.350,0:04:55.174
at what point would you ideally[br]want to intervene?

0:04:55.174,0:04:59.062
Many scientists are betting big[br]on the simplest solution:

0:04:59.062,0:05:02.852
keep amyloid plaques[br]from reaching that tipping point,

0:05:02.852,0:05:06.282
which means that drug discovery[br]is largely focused on developing

0:05:06.282,0:05:08.279
a compound that will prevent,

0:05:08.279,0:05:13.019
eliminate, or reduce[br]amyloid plaque accumulation.

0:05:13.019,0:05:14.805
And so the cure for Alzheimer's

0:05:14.805,0:05:18.072
will likely be a preventative medicine.

0:05:18.072,0:05:21.447
We're going to have to take this pill[br]before we reach that tipping point,

0:05:21.447,0:05:23.801
before the cascade is triggered,

0:05:23.801,0:05:27.381
before we start leaving[br]our keys in the refrigerator.

0:05:27.381,0:05:32.339
We think this is why, to date, these kinds[br]of drugs have failed in clinical trials,

0:05:32.339,0:05:35.153
not because the science wasn't sound,

0:05:35.153,0:05:36.759
but because the people in these trials

0:05:36.759,0:05:39.194
were already symptomatic.

0:05:39.194,0:05:40.722
It was too late.

0:05:40.722,0:05:43.892
Think of amyloid plaques as a lit match.

0:05:43.892,0:05:47.812
At the tipping point, the match[br]sets fire to the forest.

0:05:47.812,0:05:49.858
Once the forest is ablaze,

0:05:49.858,0:05:52.504
it doesn't do any good[br]to blow out the match.

0:05:52.504,0:05:56.200
You have to blow out the match[br]before the forest catches fire.

0:05:56.200,0:05:58.440
Even before scientists sort this out,

0:05:58.440,0:06:01.491
this information is actually[br]really good news for us,

0:06:01.491,0:06:04.149
because it turns out that the way[br]we live can influence

0:06:04.149,0:06:06.431
the accumulation of amyloid plaques.

0:06:06.431,0:06:08.031
And so there are things we can do

0:06:08.031,0:06:10.690
to keep us from reaching[br]that tipping point.

0:06:10.690,0:06:13.280
Let's picture your risk of Alzheimer's

0:06:13.280,0:06:15.272
as a see-saw scale.

0:06:15.272,0:06:16.877
We're going to pile[br]risk factors on one arm,

0:06:16.877,0:06:19.358
and when that arm hits the floor,[br]you are symptomatic

0:06:19.358,0:06:22.058
and diagnosed with Alzheimer's.

0:06:22.058,0:06:24.801
Let's imagine you're 50 years old.

0:06:24.801,0:06:26.560
You're not a spring chicken anymore,

0:06:26.560,0:06:29.578
so you've accumulated[br]some amyloid plaques with age.

0:06:29.578,0:06:32.058
You're scale is tipped a little bit.

0:06:32.058,0:06:34.174
Now let's look at your DNA.

0:06:34.174,0:06:38.112
We've all inherited our genes[br]from our moms and our dads.

0:06:38.112,0:06:40.314
Some of these genes will increase our risk

0:06:40.314,0:06:42.077
and some will decrease it.

0:06:42.077,0:06:44.427
If you're like Alice in "Still Alice,"

0:06:44.427,0:06:46.728
you've inherited a rare genetic mutation

0:06:46.728,0:06:49.002
that cranks out amyloid beta,

0:06:49.002,0:06:52.579
and this alone will tip[br]your scale arm to the ground.

0:06:52.579,0:06:56.433
But for most of us, the genes[br]we inherit will only tip the arm a bit.

0:06:56.433,0:06:59.042
For example, APOE4 is a gene variant

0:06:59.042,0:07:01.270
that increases amyloid,

0:07:01.270,0:07:04.900
but you can inherit a copy of APOE4[br]from mom and dad

0:07:04.900,0:07:07.315
and still never get Alzheimer's,

0:07:07.315,0:07:10.346
which means that for most of us,

0:07:10.346,0:07:14.024
our DNA alone does not determine[br]whether we get Alzheimer's.

0:07:14.024,0:07:15.521
So what does?

0:07:15.521,0:07:17.475
We can't do anything about getting older

0:07:17.475,0:07:19.370
or the genes we've inherited.

0:07:19.370,0:07:22.648
So far, we haven't changed[br]our brain's destiny.

0:07:22.648,0:07:25.897
What about sleep?

0:07:25.897,0:07:28.219
In slow-wave deep sleep,[br]our glial cells

0:07:28.219,0:07:30.557
rinse cerebral spinal fluid[br]throughout our brains

0:07:30.557,0:07:34.220
clearing away metabolic waste[br]that accumulated in our synapses

0:07:34.220,0:07:36.252
while we were awake.

0:07:36.252,0:07:40.028
Deep sleep is like[br]a power cleanse for the brain.

0:07:40.028,0:07:43.238
But what happens if you short-change[br]yourself on sleep?

0:07:43.238,0:07:46.883
Many scientists believe[br]that poor sleep hygiene

0:07:46.883,0:07:49.804
might actually be[br]a predictor of Alzheimer's.

0:07:49.804,0:07:54.754
A single night of sleep deprivation[br]leads to an increase in amyloid beta.

0:07:54.754,0:07:59.036
And amyloid accumulation[br]has been shown to disrupt sleep,

0:07:59.036,0:08:01.506
which in turn causes[br]more amyloid to accumulate.

0:08:01.506,0:08:04.005
And so now we have[br]this positive feedback loop

0:08:04.005,0:08:07.482
that's going to accelerate[br]the tipping of that scale.

0:08:07.482,0:08:09.725
What else?

0:08:09.725,0:08:11.210
Cardiovascular health.

0:08:11.210,0:08:14.837
High blood pressure, diabetes,[br]obesity, smoking, high cholesterol,

0:08:14.837,0:08:18.830
have all been shown to increase[br]our risk of developing Alzheimer's.

0:08:18.830,0:08:22.759
Some autopsy studies have shown[br]that as many as 80 percent

0:08:22.759,0:08:26.491
of people with Alzheimer's[br]also had cardiovascular disease.

0:08:26.491,0:08:29.453
Aerobic exercise has been shown[br]in many studies

0:08:29.453,0:08:31.398
to decrease amyloid beta

0:08:31.398,0:08:33.803
in animal models of the disease.

0:08:33.803,0:08:37.571
So a heart-healthy Mediterranean[br]lifestyle and diet

0:08:37.571,0:08:40.769
can help to counter[br]the tipping of this scale.

0:08:40.769,0:08:44.324
Okay, so there are many things[br]we can do to prevent

0:08:44.324,0:08:45.645
or delay the onset of Alzheimer's,

0:08:45.645,0:08:48.032
but let's say you haven't[br]done any of them.

0:08:48.032,0:08:50.631
Let's say you're 65,

0:08:50.631,0:08:54.215
there's Alzheimer's in your family,[br]so you've likely inherited a gene or two

0:08:54.215,0:08:56.303
that tips your scale arm a bit,

0:08:56.303,0:08:59.183
you've been burning the candle[br]at both ends for years,

0:08:59.183,0:09:00.710
you love bacon,

0:09:00.710,0:09:04.063
and you don't run unless[br]someone's chasing you.

0:09:04.063,0:09:07.918
Let's imagine that your amyloid plaques[br]have reached that tipping point.

0:09:07.918,0:09:09.990
Your scale arm has crashed to the floor.

0:09:09.990,0:09:11.695
You've tripped the cascade,

0:09:11.695,0:09:13.285
setting fire to the forest,

0:09:13.285,0:09:16.619
causing inflammation, tangles,[br]and cell death.

0:09:16.619,0:09:19.820
You should be symptomatic for Alzheimer's.

0:09:19.820,0:09:23.160
You should be having trouble[br]finding words and keys

0:09:23.160,0:09:26.917
and remember what I said[br]at the beginning of this talk.

0:09:26.917,0:09:29.288
But you might not be.

0:09:29.288,0:09:31.765
There's one more thing you can do[br]to protect yourself

0:09:31.765,0:09:33.984
from experiencing[br]the symptoms of Alzheimer's

0:09:33.984,0:09:38.326
even if you have the full-blown disease[br]pathology ablaze in your brain.

0:09:38.326,0:09:42.979
It has to do with neural plasticity[br]and cognitive reserve.

0:09:42.979,0:09:45.413
Remember, the experience[br]of having Alzheimer's

0:09:45.413,0:09:49.339
is ultimately a result of losing synapses.

0:09:49.339,0:09:52.835
The average brain has[br]over a hundred trillion synapses,

0:09:52.835,0:09:55.318
which is fantastic. We've got[br]a lot to work with.

0:09:55.318,0:09:57.170
And this isn't a static number.

0:09:57.170,0:10:00.514
We gain and lose synapses[br]all the time through a process

0:10:00.514,0:10:02.215
called neural plasticity.

0:10:02.215,0:10:04.515
Every time we learn something new,

0:10:04.515,0:10:08.332
we are creating and strengthening[br]new neural connections,

0:10:08.332,0:10:10.996
new synapses.

0:10:10.996,0:10:13.397
In the nun study,

0:10:13.397,0:10:13.647
678 nuns,

0:10:13.647,0:10:17.389
all over the age of 75[br]when the study began,

0:10:17.389,0:10:19.915
were followed for more than two decades.

0:10:19.915,0:10:23.321
They were regularly given[br]physical checkups and cognitive tests

0:10:23.321,0:10:27.053
and when they died, their brains[br]were all donated for autopsy.

0:10:27.053,0:10:31.792
In some of these brains, scientists[br]discovered something surprising.

0:10:31.792,0:10:36.248
Despite the presence of plaques[br]and tangles and brain shrinkage,

0:10:36.248,0:10:39.285
what appeared to be[br]unquestionable Alzheimer's,

0:10:39.285,0:10:41.793
the nuns who had belonged to these brains

0:10:41.793,0:10:46.292
showed no signs of having the disease[br]while they were alive.

0:10:46.292,0:10:48.176
How can this be?

0:10:48.176,0:10:51.972
We think it is because these nuns[br]had a high level of cognitive reserve,

0:10:51.972,0:10:56.107
which is a way of saying that they had[br]more functional synapses.

0:10:56.107,0:10:58.551
People who have more years[br]of formal education,

0:10:58.551,0:11:00.964
who have a high degree of literacy,

0:11:00.964,0:11:04.567
who engage regularly[br]in mentally stimulating activities,

0:11:04.567,0:11:07.072
all have more cognitive reserve.

0:11:07.072,0:11:11.107
They have an abundance[br]and a redundancy in neural connections.

0:11:11.107,0:11:13.621
So even if they have a disease[br]like Alzheimer's

0:11:13.621,0:11:16.005
compromising some of their synapses,

0:11:16.005,0:11:19.329
they've got many extra backup connections,

0:11:19.329,0:11:23.041
and this buffers them from noticing[br]that anything is amiss.

0:11:23.041,0:11:25.427
Let's imagine a simplified example.

0:11:25.427,0:11:28.176
Let's say you only know one thing[br]about a subject.

0:11:28.176,0:11:29.728
Let's say it's about me.

0:11:29.728,0:11:32.057
You know that Lisa Genova[br]wrote "Still Alice,"

0:11:32.057,0:11:34.597
and that's the only thing[br]you know about me.

0:11:34.597,0:11:36.916
You have that single neural connection,

0:11:36.916,0:11:38.885
that one synapse.

0:11:38.885,0:11:40.748
Now imagine you have Alzheimer's.

0:11:40.748,0:11:43.445
You have plaques and tangles[br]and inflammation

0:11:43.445,0:11:46.627
and microglia devouring that synapse.

0:11:46.627,0:11:50.087
Now, when someone asks you,[br]"Hey, who wrote 'Still Alice?'"

0:11:50.087,0:11:55.333
you can't remember, because[br]that synapse is either failing or gone.

0:11:55.333,0:11:57.760
You've forgotten me forever.

0:11:57.760,0:12:00.239
But what if you had learned more about me?

0:12:00.239,0:12:02.533
Let's say you learned[br]four things about me.

0:12:02.533,0:12:05.290
Now imagine you have Alzheimer's,

0:12:05.290,0:12:07.983
and three of those synapses[br]are damaged or destroyed.

0:12:07.983,0:12:10.733
You still have a way[br]to detour the wreckage.

0:12:10.733,0:12:13.394
You can still remember my name.

0:12:13.394,0:12:17.233
So we can be resilient[br]to the presence of Alzheimer's pathology

0:12:17.233,0:12:20.360
through the recruitment of[br]yet undamaged pathways,

0:12:20.360,0:12:22.332
and we create these pathways,

0:12:22.332,0:12:24.163
this cognitive reserve,

0:12:24.163,0:12:26.709
by learning new things.

0:12:26.709,0:12:31.000
Now ideally we want these new things[br]to be as rich in meaning as possible,

0:12:31.000,0:12:35.763
recruiting sight and sound[br]and associations and emotion.

0:12:35.763,0:12:39.382
So this really doesn't mean[br]doing crossword puzzles.

0:12:39.382,0:12:43.556
You don't want to simply retrieve[br]information you've already learned,

0:12:43.556,0:12:47.045
because this is like traveling[br]down old, familiar streets,

0:12:47.045,0:12:49.697
cruising neighborhoods you already know.

0:12:49.697,0:12:52.554
You want to pave new neural roads.

0:12:52.554,0:12:55.111
Building an Alzheimer's-resistant brain

0:12:55.111,0:12:57.314
means learning to speak Italian,

0:12:57.314,0:12:59.245
meeting new friends,

0:12:59.245,0:13:00.560
reading a book,

0:13:00.560,0:13:03.386
or listening to a great TEDTalk.

0:13:03.386,0:13:08.577
And if despite all of this, you are[br]someday diagnosed with Alzheimer's,

0:13:08.577,0:13:11.353
there are three lessons I've learned[br]from my grandmother

0:13:11.353,0:13:16.282
and the dozens of people I've come[br]to know living with this disease.

0:13:16.282,0:13:19.124
Diagnosis doesn't mean[br]you're dying tomorrow.

0:13:19.124,0:13:20.869
Keep living.

0:13:20.869,0:13:23.251
You won't lose your emotional memory.

0:13:23.251,0:13:26.780
You'll still be able to understand[br]love and joy.

0:13:26.780,0:13:30.016
You might not remember what I said[br]five minutes ago,

0:13:30.016,0:13:32.672
but you'll remember[br]how I made you feel.

0:13:32.672,0:13:36.369
And you are more than what[br]you can remember.

0:13:36.369,0:13:37.836
Thank you.

0:13:37.836,0:13:43.159
(Applause)