0:00:01.117,0:00:05.531
How many people here would like to live[br]to be at least 80 years old?

0:00:06.072,0:00:07.547
Yeah.

0:00:07.571,0:00:10.366
I think we all have[br]this hopeful expectation

0:00:10.390,0:00:12.350
of living into old age.

0:00:12.828,0:00:14.914
Let's project out into the future,

0:00:14.938,0:00:16.498
to your future You's,

0:00:16.522,0:00:19.375
and let's imagine that we're all 85.

0:00:19.894,0:00:21.912
Now, everyone look at two people.

0:00:23.151,0:00:26.683
One of you probably has[br]Alzheimer's disease.

0:00:27.365,0:00:30.789
(Laughter)

0:00:30.813,0:00:32.407
Alright, alright.

0:00:32.954,0:00:36.771
And maybe you're thinking,[br]"Well, it won't be me."

0:00:37.350,0:00:40.735
Then, OK. You are a caregiver.

0:00:41.388,0:00:42.552
So --

0:00:42.576,0:00:45.448
(Laughter)

0:00:45.472,0:00:46.829
so in some way,

0:00:46.853,0:00:50.497
this terrifying disease[br]is likely to affect us all.

0:00:50.933,0:00:53.947
Part of the fear around Alzheimer's[br]stems from the sense

0:00:53.971,0:00:56.385
that there's nothing we can do about it.

0:00:56.409,0:01:01.534
Despite decades of research, we still[br]have no disease-modifying treatment

0:01:01.558,0:01:02.865
and no cure.

0:01:03.321,0:01:05.790
So if we're lucky enough[br]to live long enough,

0:01:05.814,0:01:08.922
Alzheimer's appears to be[br]our brain's destiny.

0:01:09.369,0:01:11.249
But maybe it doesn't have to be.

0:01:11.585,0:01:14.950
What if I told you we could[br]change these statistics,

0:01:14.974,0:01:17.664
literally change our brain's destiny,

0:01:17.688,0:01:21.217
without relying on a cure[br]or advancements in medicine?

0:01:21.983,0:01:24.508
Let's begin by looking at[br]what we currently understand

0:01:24.532,0:01:26.889
about the neuroscience of Alzheimer's.

0:01:27.730,0:01:30.739
Here's a picture[br]of two neurons connecting.

0:01:30.763,0:01:34.120
The point of connection,[br]this space circled in red,

0:01:34.144,0:01:35.783
is called the synapse.

0:01:35.807,0:01:38.999
The synapse is where[br]neurotransmitters are released.

0:01:39.023,0:01:43.291
This is where signals are transmitted,[br]where communication happens.

0:01:43.315,0:01:48.421
This is where we think,[br]feel, see, hear, desire ...

0:01:48.445,0:01:50.094
and remember.

0:01:50.118,0:01:53.016
And the synapse[br]is where Alzheimer's happens.

0:01:53.040,0:01:55.002
Let's zoom in on the synapse

0:01:55.026,0:01:58.113
and look at a cartoon representation[br]of what's going on.

0:01:58.799,0:02:01.086
During the business[br]of communicating information,

0:02:01.110,0:02:05.108
in addition to releasing neurotransmitters[br]like glutamate into the synapse,

0:02:05.132,0:02:09.593
neurons also release a small peptide[br]called amyloid beta.

0:02:10.617,0:02:15.601
Normally, amyloid beta is cleared away[br]metabolized by microglia,

0:02:15.625,0:02:17.778
the janitor cells of our brains.

0:02:18.405,0:02:22.264
While the molecular causes[br]of Alzheimer's are still debated,

0:02:22.288,0:02:25.542
most neuroscientists believe[br]that the disease begins

0:02:25.566,0:02:28.396
when amyloid beta begins to accumulate.

0:02:28.967,0:02:31.716
Too much is released,[br]or not enough is cleared away,

0:02:31.740,0:02:35.074
and the synapse begins[br]to pile up with amyloid beta.

0:02:35.098,0:02:37.317
And when this happens, it binds to itself,

0:02:37.341,0:02:40.630
forming sticky aggregates[br]called amyloid plaques.

0:02:41.582,0:02:44.535
How many people here[br]are 40 years old or older?

0:02:45.184,0:02:47.704
You're afraid to admit it now.

0:02:47.728,0:02:49.954
This initial step into the disease,

0:02:49.978,0:02:53.062
this presence of amyloid[br]plaques accumulating,

0:02:53.086,0:02:55.680
can already be found in your brains.

0:02:56.271,0:02:59.741
The only way we could be sure of this[br]would be through a PET scan,

0:02:59.765,0:03:03.581
because at this point,[br]you are blissfully unaware.

0:03:03.605,0:03:07.894
You're not showing any impairments[br]in memory, language, or cognition ...

0:03:07.918,0:03:09.069
yet.

0:03:09.471,0:03:14.008
We think it takes at least 15 to 20 years[br]of amyloid plaque accumulation

0:03:14.032,0:03:16.413
before it reaches a tipping point,

0:03:16.437,0:03:18.672
then triggering a molecular cascade

0:03:18.696,0:03:21.363
that causes the clinical[br]symptoms of the disease.

0:03:21.810,0:03:23.771
Prior to the tipping point,

0:03:23.795,0:03:27.379
your lapses in memory[br]might include things like,

0:03:27.403,0:03:29.728
"Why did I come in this room?"

0:03:29.752,0:03:31.980
or "Oh ... what's his name?"

0:03:32.479,0:03:34.823
or "Where did I put my keys?"

0:03:35.553,0:03:38.109
Now, before you all[br]start freaking out again,

0:03:38.133,0:03:43.531
because I know half of you did at least[br]one of those in the last 24 hours --

0:03:43.555,0:03:46.792
these are all normal kinds of forgetting.

0:03:46.816,0:03:49.129
In fact, I would argue that these examples

0:03:49.153,0:03:51.130
might not even involve your memory,

0:03:51.154,0:03:54.046
because you didn't pay attention[br]to where you put your keys

0:03:54.070,0:03:55.415
in the first place.

0:03:55.439,0:03:57.117
After the tipping point,

0:03:57.141,0:04:00.664
the glitches in memory,[br]language and cognition are different.

0:04:00.688,0:04:03.588
Instead of eventually finding[br]your keys in your coat pocket

0:04:03.612,0:04:05.614
or on the table by the door,

0:04:05.638,0:04:08.352
you find them in the refrigerator,

0:04:08.376,0:04:10.342
or you find them and you think,

0:04:10.366,0:04:11.899
"What are these for?"

0:04:12.843,0:04:18.051
So what happens when amyloid plaques[br]accumulate to this tipping point?

0:04:18.075,0:04:21.394
Our microglia janitor cells[br]become hyper-activated,

0:04:21.418,0:04:25.552
releasing chemicals that cause[br]inflammation and cellular damage.

0:04:25.576,0:04:28.171
We think they might actually[br]start clearing away

0:04:28.195,0:04:29.899
the synapses themselves.

0:04:30.398,0:04:34.846
A crucial neural transport protein[br]called "tau" becomes hyperphosphorylated

0:04:34.870,0:04:37.454
and twists itself[br]into something called "tangles,"

0:04:37.478,0:04:40.513
which choke off the neurons[br]from the inside.

0:04:40.537,0:04:44.371
By mid-stage Alzheimer's,[br]we have massive inflammation and tangles

0:04:44.395,0:04:46.342
and all-out war at the synapse

0:04:46.366,0:04:47.619
and cell death.

0:04:48.238,0:04:51.326
So if you were a scientist[br]trying to cure this disease,

0:04:51.350,0:04:54.347
at what point would you ideally[br]want to intervene?

0:04:55.134,0:04:59.038
Many scientists are betting big[br]on the simplest solution:

0:04:59.062,0:05:02.896
keep amyloid plaques[br]from reaching that tipping point,

0:05:02.920,0:05:06.948
which means that drug discovery is largely[br]focused on developing a compound

0:05:06.972,0:05:12.320
that will prevent, eliminate, or reduce[br]amyloid plaque accumulation.

0:05:12.859,0:05:18.048
So the cure for Alzheimer's will likely be[br]a preventative medicine.

0:05:18.072,0:05:21.501
We're going to have to take this pill[br]before we reach that tipping point,

0:05:21.525,0:05:23.777
before the cascade is triggered,

0:05:23.801,0:05:26.829
before we start leaving[br]our keys in the refrigerator.

0:05:27.381,0:05:31.054
We think this is why, to date,[br]these kinds of drugs have failed

0:05:31.078,0:05:32.315
in clinical trials --

0:05:32.339,0:05:34.784
not because the science wasn't sound,

0:05:34.808,0:05:38.942
but because the people in these trials[br]were already symptomatic.

0:05:38.966,0:05:40.698
It was too late.

0:05:40.722,0:05:43.974
Think of amyloid plaques as a lit match.

0:05:43.998,0:05:47.416
At the tipping point, the match[br]sets fire to the forest.

0:05:47.884,0:05:49.834
Once the forest is ablaze,

0:05:49.858,0:05:52.340
it doesn't do any good[br]to blow out the match.

0:05:52.364,0:05:55.887
You have to blow out the match[br]before the forest catches fire.

0:05:56.331,0:05:58.194
Even before scientists sort this out,

0:05:58.218,0:06:01.086
this information is actually[br]really good news for us,

0:06:01.110,0:06:05.154
because it turns out that the way we live[br]can influence the accumulation

0:06:05.178,0:06:06.407
of amyloid plaques.

0:06:06.431,0:06:08.007
And so there are things we can do

0:06:08.031,0:06:10.650
to keep us from reaching[br]that tipping point.

0:06:11.117,0:06:15.005
Let's picture your risk[br]of Alzheimer's as a see-saw scale.

0:06:15.029,0:06:17.078
We're going to pile[br]risk factors on one arm,

0:06:17.102,0:06:19.580
and when that arm hits the floor,[br]you are symptomatic

0:06:19.604,0:06:21.539
and diagnosed with Alzheimer's.

0:06:22.058,0:06:24.777
Let's imagine you're 50 years old.

0:06:24.801,0:06:26.536
You're not a spring chicken anymore,

0:06:26.560,0:06:29.632
so you've accumulated[br]some amyloid plaques with age.

0:06:29.656,0:06:31.847
Your scale is tipped a little bit.

0:06:32.323,0:06:34.062
Now let's look at your DNA.

0:06:34.536,0:06:38.088
We've all inherited our genes[br]from our moms and our dads.

0:06:38.112,0:06:42.190
Some of these genes will increase our risk[br]and some will decrease it.

0:06:42.214,0:06:44.403
If you're like Alice in "Still Alice,"

0:06:44.427,0:06:48.978
you've inherited a rare genetic mutation[br]that cranks out amyloid beta,

0:06:49.002,0:06:52.555
and this alone will tip[br]your scale arm to the ground.

0:06:52.579,0:06:56.745
But for most of us, the genes we inherit[br]will only tip the arm a bit.

0:06:56.769,0:07:01.584
For example, APOE4 is a gene variant[br]that increases amyloid,

0:07:01.608,0:07:04.876
but you can inherit a copy of APOE4[br]from mom and dad

0:07:04.900,0:07:07.291
and still never get Alzheimer's,

0:07:07.315,0:07:09.428
which means that for most of us,

0:07:09.452,0:07:13.292
our DNA alone does not determine[br]whether we get Alzheimer's.

0:07:13.984,0:07:15.458
So what does?

0:07:15.482,0:07:19.274
We can't do anything about getting older[br]or the genes we've inherited.

0:07:19.298,0:07:22.295
So far, we haven't changed[br]our brain's destiny.

0:07:23.144,0:07:24.609
What about sleep?

0:07:25.278,0:07:29.360
In slow-wave deep sleep, our glial cells[br]rinse cerebral spinal fluid

0:07:29.384,0:07:30.600
throughout our brains,

0:07:30.624,0:07:34.196
clearing away metabolic waste[br]that accumulated in our synapses

0:07:34.220,0:07:36.121
while we were awake.

0:07:36.145,0:07:38.951
Deep sleep is like[br]a power cleanse for the brain.

0:07:39.646,0:07:42.832
But what happens if you shortchange[br]yourself on sleep?

0:07:43.421,0:07:44.953
Many scientists believe

0:07:44.977,0:07:49.227
that poor sleep hygiene might actually[br]be a predictor of Alzheimer's.

0:07:49.613,0:07:54.539
A single night of sleep deprivation[br]leads to an increase in amyloid beta.

0:07:55.410,0:07:58.836
And amyloid accumulation[br]has been shown to disrupt sleep,

0:07:58.860,0:08:01.347
which in turn causes[br]more amyloid to accumulate.

0:08:01.371,0:08:03.847
And so now we have[br]this positive feedback loop

0:08:03.871,0:08:06.744
that's going to accelerate[br]the tipping of that scale.

0:08:07.306,0:08:08.729
What else?

0:08:08.753,0:08:10.379
Cardiovascular health.

0:08:11.043,0:08:14.788
High blood pressure, diabetes,[br]obesity, smoking, high cholesterol,

0:08:14.812,0:08:18.948
have all been shown to increase our risk[br]of developing Alzheimer's.

0:08:18.972,0:08:20.863
Some autopsy studies have shown

0:08:20.887,0:08:23.559
that as many as 80 percent[br]of people with Alzheimer's

0:08:23.583,0:08:26.345
also had cardiovascular disease.

0:08:26.369,0:08:31.374
Aerobic exercise has been shown[br]in many studies to decrease amyloid beta

0:08:31.398,0:08:33.128
in animal models of the disease.

0:08:33.619,0:08:37.199
So a heart-healthy[br]Mediterranean lifestyle and diet

0:08:37.223,0:08:39.877
can help to counter[br]the tipping of this scale.

0:08:40.697,0:08:43.046
So there are many things we can do

0:08:43.070,0:08:45.442
to prevent or delay[br]the onset of Alzheimer's.

0:08:45.466,0:08:47.695
But let's say[br]you haven't done any of them.

0:08:48.211,0:08:50.665
Let's say you're 65;

0:08:50.689,0:08:54.355
there's Alzheimer's in your family,[br]so you've likely inherited a gene or two

0:08:54.379,0:08:56.403
that tips your scale arm a bit;

0:08:56.427,0:08:59.159
you've been burning the candle[br]at both ends for years;

0:08:59.183,0:09:00.686
you love bacon;

0:09:00.710,0:09:02.933
and you don't run unless[br]someone's chasing you.

0:09:02.957,0:09:04.258
(Laughter)

0:09:04.282,0:09:07.894
Let's imagine that your amyloid plaques[br]have reached that tipping point.

0:09:07.918,0:09:09.966
Your scale arm has crashed to the floor.

0:09:09.990,0:09:11.671
You've tripped the cascade,

0:09:11.695,0:09:13.261
setting fire to the forest,

0:09:13.285,0:09:16.383
causing inflammation, tangles,[br]and cell death.

0:09:17.137,0:09:19.796
You should be symptomatic for Alzheimer's.

0:09:19.820,0:09:23.136
You should be having trouble[br]finding words and keys

0:09:23.160,0:09:26.306
and remembering what I said[br]at the beginning of this talk.

0:09:26.917,0:09:28.631
But you might not be.

0:09:29.180,0:09:31.658
There's one more thing you can do[br]to protect yourself

0:09:31.682,0:09:34.268
from experiencing[br]the symptoms of Alzheimer's,

0:09:34.292,0:09:38.783
even if you have the full-blown disease[br]pathology ablaze in your brain.

0:09:38.807,0:09:42.714
It has to do with neural plasticity[br]and cognitive reserve.

0:09:43.261,0:09:45.638
Remember, the experience[br]of having Alzheimer's

0:09:45.662,0:09:48.868
is ultimately a result of losing synapses.

0:09:49.339,0:09:52.716
The average brain has[br]over a hundred trillion synapses,

0:09:52.740,0:09:55.453
which is fantastic;[br]we've got a lot to work with.

0:09:55.477,0:09:57.146
And this isn't a static number.

0:09:57.170,0:09:59.568
We gain and lose synapses all the time,

0:09:59.592,0:10:02.395
through a process[br]called neural plasticity.

0:10:02.419,0:10:04.491
Every time we learn something new,

0:10:04.515,0:10:08.642
we are creating and strengthening[br]new neural connections,

0:10:08.666,0:10:10.283
new synapses.

0:10:10.988,0:10:12.563
In the Nun Study,

0:10:12.587,0:10:17.480
678 nuns, all over the age of 75[br]when the study began,

0:10:17.504,0:10:19.813
were followed for more than two decades.

0:10:19.837,0:10:23.297
They were regularly given[br]physical checkups and cognitive tests,

0:10:23.321,0:10:27.369
and when they died, their brains[br]were all donated for autopsy.

0:10:27.393,0:10:31.768
In some of these brains, scientists[br]discovered something surprising.

0:10:31.792,0:10:36.368
Despite the presence of plaques[br]and tangles and brain shrinkage --

0:10:36.392,0:10:39.261
what appeared to be[br]unquestionable Alzheimer's --

0:10:39.285,0:10:42.964
the nuns who had belonged[br]to these brains showed no signs

0:10:42.988,0:10:45.555
of having the disease[br]while they were alive.

0:10:46.181,0:10:47.630
How can this be?

0:10:48.009,0:10:52.136
We think it's because these nuns[br]had a high level of cognitive reserve,

0:10:52.160,0:10:56.083
which is a way of saying that they had[br]more functional synapses.

0:10:56.107,0:10:58.681
People who have more years[br]of formal education,

0:10:58.705,0:11:00.940
who have a high degree of literacy,

0:11:00.964,0:11:04.543
who engage regularly[br]in mentally stimulating activities,

0:11:04.567,0:11:07.048
all have more cognitive reserve.

0:11:07.072,0:11:11.199
They have an abundance[br]and a redundancy in neural connections.

0:11:11.223,0:11:13.903
So even if they have a disease[br]like Alzheimer's

0:11:13.927,0:11:15.981
compromising some of their synapses,

0:11:16.005,0:11:18.990
they've got many extra backup connections,

0:11:19.014,0:11:22.349
and this buffers them from noticing[br]that anything is amiss.

0:11:22.977,0:11:25.239
Let's imagine a simplified example.

0:11:25.263,0:11:27.989
Let's say you only know one thing[br]about a subject.

0:11:28.013,0:11:29.542
Let's say it's about me.

0:11:29.566,0:11:31.872
You know that Lisa Genova[br]wrote "Still Alice,"

0:11:31.896,0:11:34.332
and that's the only thing[br]you know about me.

0:11:34.356,0:11:36.746
You have that single neural connection,

0:11:36.770,0:11:38.716
that one synapse.

0:11:38.740,0:11:40.901
Now imagine you have Alzheimer's.

0:11:40.925,0:11:43.258
You have plaques and tangles[br]and inflammation

0:11:43.282,0:11:46.017
and microglia devouring that synapse.

0:11:46.603,0:11:50.833
Now when someone asks you,[br]"Hey, who wrote 'Still Alice?'"

0:11:50.857,0:11:52.102
you can't remember,

0:11:52.126,0:11:55.309
because that synapse[br]is either failing or gone.

0:11:55.333,0:11:57.092
You've forgotten me forever.

0:11:57.760,0:12:00.386
But what if you had learned more about me?

0:12:00.410,0:12:02.499
Let's say you learned[br]four things about me.

0:12:02.523,0:12:04.368
Now imagine you have Alzheimer's,

0:12:04.392,0:12:07.387
and three of those synapses[br]are damaged or destroyed.

0:12:08.077,0:12:10.538
You still have a way[br]to detour the wreckage.

0:12:10.562,0:12:12.581
You can still remember my name.

0:12:13.283,0:12:17.209
So we can be resilient[br]to the presence of Alzheimer's pathology

0:12:17.233,0:12:20.336
through the recruitment[br]of yet-undamaged pathways.

0:12:20.360,0:12:24.139
And we create these pathways,[br]this cognitive reserve,

0:12:24.163,0:12:25.863
by learning new things.

0:12:26.455,0:12:30.976
Ideally, we want these new things[br]to be as rich in meaning as possible,

0:12:31.000,0:12:35.739
recruiting sight and sound[br]and associations and emotion.

0:12:36.398,0:12:39.533
So this really doesn't mean[br]doing crossword puzzles.

0:12:39.557,0:12:43.654
You don't want to simply retrieve[br]information you've already learned,

0:12:43.678,0:12:47.021
because this is like traveling[br]down old, familiar streets,

0:12:47.045,0:12:49.630
cruising neighborhoods you already know.

0:12:50.113,0:12:52.947
You want to pave new neural roads.

0:12:52.971,0:12:55.483
Building an Alzheimer's-resistant brain

0:12:55.507,0:12:57.687
means learning to speak Italian,

0:12:57.711,0:12:59.221
meeting new friends,

0:12:59.245,0:13:00.412
reading a book,

0:13:00.436,0:13:02.805
or listening to a great TED Talk.

0:13:03.283,0:13:08.596
And if, despite all of this, you are[br]someday diagnosed with Alzheimer's,

0:13:08.620,0:13:11.773
there are three lessons I've learned[br]from my grandmother

0:13:11.797,0:13:15.534
and the dozens of people I've come to know[br]living with this disease.

0:13:16.115,0:13:19.299
Diagnosis doesn't mean[br]you're dying tomorrow.

0:13:19.323,0:13:21.045
Keep living.

0:13:21.069,0:13:23.435
You won't lose your emotional memory.

0:13:23.459,0:13:26.965
You'll still be able[br]to understand love and joy.

0:13:26.989,0:13:29.992
You might not remember[br]what I said five minutes ago,

0:13:30.016,0:13:32.301
but you'll remember how I made you feel.

0:13:32.944,0:13:36.220
And you are more than what[br]you can remember.

0:13:36.244,0:13:37.533
Thank you.

0:13:37.557,0:13:42.880
(Applause)