1
00:00:01,117 --> 00:00:05,531
How many people here would like to live
to be at least 80 years old?

2
00:00:06,072 --> 00:00:07,547
Yeah.

3
00:00:07,571 --> 00:00:10,366
I think we all have
this hopeful expectation

4
00:00:10,390 --> 00:00:12,350
of living into old age.

5
00:00:12,828 --> 00:00:14,914
Let's project out into the future,

6
00:00:14,938 --> 00:00:16,498
to your future "you's,"

7
00:00:16,522 --> 00:00:19,375
and let's imagine that we're all 85.

8
00:00:19,894 --> 00:00:21,912
Now, everyone look at two people.

9
00:00:23,151 --> 00:00:26,683
One of you probably has
Alzheimer's disease.

10
00:00:27,365 --> 00:00:30,789
(Laughter)

11
00:00:30,813 --> 00:00:32,407
Alright, alright.

12
00:00:32,954 --> 00:00:36,771
And maybe you're thinking,
"Well, it won't be me."

13
00:00:37,350 --> 00:00:40,735
Then, OK. You are a caregiver.

14
00:00:41,388 --> 00:00:42,552
So --

15
00:00:42,576 --> 00:00:45,448
(Laughter)

16
00:00:45,472 --> 00:00:46,829
so in some way,

17
00:00:46,853 --> 00:00:50,497
this terrifying disease
is likely to affect us all.

18
00:00:50,933 --> 00:00:53,947
Part of the fear around Alzheimer's
stems from the sense

19
00:00:53,971 --> 00:00:56,385
that there's nothing we can do about it.

20
00:00:56,409 --> 00:01:01,534
Despite decades of research, we still
have no disease-modifying treatment

21
00:01:01,558 --> 00:01:02,865
and no cure.

22
00:01:03,321 --> 00:01:05,790
So if we're lucky enough
to live long enough,

23
00:01:05,814 --> 00:01:08,922
Alzheimer's appears to be
our brain's destiny.

24
00:01:09,369 --> 00:01:11,249
But maybe it doesn't have to be.

25
00:01:11,585 --> 00:01:14,950
What if I told you we could
change these statistics,

26
00:01:14,974 --> 00:01:17,664
literally change our brain's destiny,

27
00:01:17,688 --> 00:01:21,217
without relying on a cure
or advancements in medicine?

28
00:01:21,983 --> 00:01:24,508
Let's begin by looking at
what we currently understand

29
00:01:24,532 --> 00:01:26,889
about the neuroscience of Alzheimer's.

30
00:01:27,730 --> 00:01:30,739
Here's a picture
of two neurons connecting.

31
00:01:30,763 --> 00:01:34,120
The point of connection,
this space circled in red,

32
00:01:34,144 --> 00:01:35,783
is called the synapse.

33
00:01:35,807 --> 00:01:38,999
The synapse is where
neurotransmitters are released.

34
00:01:39,023 --> 00:01:43,291
This is where signals are transmitted,
where communication happens.

35
00:01:43,315 --> 00:01:48,421
This is where we think,
feel, see, hear, desire ...

36
00:01:48,445 --> 00:01:50,094
and remember.

37
00:01:50,118 --> 00:01:53,016
And the synapse
is where Alzheimer's happens.

38
00:01:53,040 --> 00:01:55,002
Let's zoom in on the synapse

39
00:01:55,026 --> 00:01:58,113
and look at a cartoon representation
of what's going on.

40
00:01:58,799 --> 00:02:01,086
During the business
of communicating information,

41
00:02:01,110 --> 00:02:05,108
in addition to releasing neurotransmitters
like glutamate into the synapse,

42
00:02:05,132 --> 00:02:09,593
neurons also release a small peptide
called amyloid beta.

43
00:02:10,617 --> 00:02:15,601
Normally, amyloid beta is cleared away
metabolized by microglia,

44
00:02:15,625 --> 00:02:17,778
the janitor cells of our brains.

45
00:02:18,405 --> 00:02:22,264
While the molecular causes
of Alzheimer's are still debated,

46
00:02:22,288 --> 00:02:25,542
most neuroscientists believe
that the disease begins

47
00:02:25,566 --> 00:02:28,396
when amyloid beta begins to accumulate.

48
00:02:28,967 --> 00:02:31,716
Too much is released,
or not enough is cleared away,

49
00:02:31,740 --> 00:02:35,074
and the synapse begins
to pile up with amyloid beta.

50
00:02:35,098 --> 00:02:37,317
And when this happens, it binds to itself,

51
00:02:37,341 --> 00:02:40,630
forming sticky aggregates
called amyloid plaques.

52
00:02:41,582 --> 00:02:44,535
How many people here
are 40 years old or older?

53
00:02:45,184 --> 00:02:47,704
You're afraid to admit it now.

54
00:02:47,728 --> 00:02:49,954
This initial step into the disease,

55
00:02:49,978 --> 00:02:53,062
this presence of amyloid
plaques accumulating,

56
00:02:53,086 --> 00:02:55,680
can already be found in your brains.

57
00:02:56,271 --> 00:02:59,741
The only way we could be sure of this
would be through a PET scan,

58
00:02:59,765 --> 00:03:03,581
because at this point,
you are blissfully unaware.

59
00:03:03,605 --> 00:03:07,894
You're not showing any impairments
in memory, language, or cognition ...

60
00:03:07,918 --> 00:03:09,069
yet.

61
00:03:09,471 --> 00:03:14,008
We think it takes at least 15 to 20 years
of amyloid plaque accumulation

62
00:03:14,032 --> 00:03:16,413
before it reaches a tipping point,

63
00:03:16,437 --> 00:03:18,672
then triggering a molecular cascade

64
00:03:18,696 --> 00:03:21,363
that causes the clinical
symptoms of the disease.

65
00:03:21,810 --> 00:03:23,771
Prior to the tipping point,

66
00:03:23,795 --> 00:03:27,379
your lapses in memory
might include things like,

67
00:03:27,403 --> 00:03:29,728
"Why did I come in this room?"

68
00:03:29,752 --> 00:03:31,980
or "Oh ... what's his name?"

69
00:03:32,479 --> 00:03:34,823
or "Where did I put my keys?"

70
00:03:35,553 --> 00:03:38,109
Now, before you all
start freaking out again,

71
00:03:38,133 --> 00:03:43,531
because I know half of you did at least
one of those in the last 24 hours --

72
00:03:43,555 --> 00:03:46,792
these are all normal kinds of forgetting.

73
00:03:46,816 --> 00:03:49,129
In fact, I would argue that these examples

74
00:03:49,153 --> 00:03:51,130
might not even involve your memory,

75
00:03:51,154 --> 00:03:54,046
because you didn't pay attention
to where you put your keys

76
00:03:54,070 --> 00:03:55,415
in the first place.

77
00:03:55,439 --> 00:03:57,117
After the tipping point,

78
00:03:57,141 --> 00:04:00,664
the glitches in memory,
language and cognition are different.

79
00:04:00,688 --> 00:04:03,588
Instead of eventually finding
your keys in your coat pocket

80
00:04:03,612 --> 00:04:05,614
or on the table by the door,

81
00:04:05,638 --> 00:04:08,352
you find them in the refrigerator,

82
00:04:08,376 --> 00:04:10,342
or you find them and you think,

83
00:04:10,366 --> 00:04:11,899
"What are these for?"

84
00:04:12,843 --> 00:04:18,051
So what happens when amyloid plaques
accumulate to this tipping point?

85
00:04:18,075 --> 00:04:21,394
Our microglia janitor cells
become hyper-activated,

86
00:04:21,418 --> 00:04:25,552
releasing chemicals that cause
inflammation and cellular damage.

87
00:04:25,576 --> 00:04:28,171
We think they might actually
start clearing away

88
00:04:28,195 --> 00:04:29,899
the synapses themselves.

89
00:04:30,398 --> 00:04:34,846
A crucial neural transport protein
called "tau" becomes hyperphosphorylated

90
00:04:34,870 --> 00:04:37,454
and twists itself
into something called "tangles,"

91
00:04:37,478 --> 00:04:40,513
which choke off the neurons
from the inside.

92
00:04:40,537 --> 00:04:44,371
By mid-stage Alzheimer's,
we have massive inflammation and tangles

93
00:04:44,395 --> 00:04:46,342
and all-out war at the synapse

94
00:04:46,366 --> 00:04:47,619
and cell death.

95
00:04:48,238 --> 00:04:51,326
So if you were a scientist
trying to cure this disease,

96
00:04:51,350 --> 00:04:54,347
at what point would you ideally
want to intervene?

97
00:04:55,134 --> 00:04:59,038
Many scientists are betting big
on the simplest solution:

98
00:04:59,062 --> 00:05:02,896
keep amyloid plaques
from reaching that tipping point,

99
00:05:02,920 --> 00:05:06,948
which means that drug discovery is largely
focused on developing a compound

100
00:05:06,972 --> 00:05:12,320
that will prevent, eliminate, or reduce
amyloid plaque accumulation.

101
00:05:12,859 --> 00:05:18,048
So the cure for Alzheimer's will likely be
a preventative medicine.

102
00:05:18,072 --> 00:05:21,501
We're going to have to take this pill
before we reach that tipping point,

103
00:05:21,525 --> 00:05:23,777
before the cascade is triggered,

104
00:05:23,801 --> 00:05:26,829
before we start leaving
our keys in the refrigerator.

105
00:05:27,381 --> 00:05:31,054
We think this is why, to date,
these kinds of drugs have failed

106
00:05:31,078 --> 00:05:32,315
in clinical trials --

107
00:05:32,339 --> 00:05:34,784
not because the science wasn't sound,

108
00:05:34,808 --> 00:05:38,942
but because the people in these trials
were already symptomatic.

109
00:05:38,966 --> 00:05:40,698
It was too late.

110
00:05:40,722 --> 00:05:43,974
Think of amyloid plaques as a lit match.

111
00:05:43,998 --> 00:05:47,416
At the tipping point, the match
sets fire to the forest.

112
00:05:47,884 --> 00:05:49,834
Once the forest is ablaze,

113
00:05:49,858 --> 00:05:52,340
it doesn't do any good
to blow out the match.

114
00:05:52,364 --> 00:05:55,887
You have to blow out the match
before the forest catches fire.

115
00:05:56,331 --> 00:05:58,194
Even before scientists sort this out,

116
00:05:58,218 --> 00:06:01,086
this information is actually
really good news for us,

117
00:06:01,110 --> 00:06:05,154
because it turns out that the way we live
can influence the accumulation

118
00:06:05,178 --> 00:06:06,407
of amyloid plaques.

119
00:06:06,431 --> 00:06:08,007
And so there are things we can do

120
00:06:08,031 --> 00:06:10,650
to keep us from reaching
that tipping point.

121
00:06:11,117 --> 00:06:15,005
Let's picture your risk
of Alzheimer's as a see-saw scale.

122
00:06:15,029 --> 00:06:17,078
We're going to pile
risk factors on one arm,

123
00:06:17,102 --> 00:06:19,580
and when that arm hits the floor,
you are symptomatic

124
00:06:19,604 --> 00:06:21,539
and diagnosed with Alzheimer's.

125
00:06:22,058 --> 00:06:24,777
Let's imagine you're 50 years old.

126
00:06:24,801 --> 00:06:26,536
You're not a spring chicken anymore,

127
00:06:26,560 --> 00:06:29,632
so you've accumulated
some amyloid plaques with age.

128
00:06:29,656 --> 00:06:31,847
Your scale is tipped a little bit.

129
00:06:32,323 --> 00:06:34,062
Now let's look at your DNA.

130
00:06:34,536 --> 00:06:38,088
We've all inherited our genes
from our moms and our dads.

131
00:06:38,112 --> 00:06:42,190
Some of these genes will increase our risk
and some will decrease it.

132
00:06:42,214 --> 00:06:44,403
If you're like Alice in "Still Alice,"

133
00:06:44,427 --> 00:06:48,978
you've inherited a rare genetic mutation
that cranks out amyloid beta,

134
00:06:49,002 --> 00:06:52,555
and this alone will tip
your scale arm to the ground.

135
00:06:52,579 --> 00:06:56,745
But for most of us, the genes we inherit
will only tip the arm a bit.

136
00:06:56,769 --> 00:07:01,584
For example, APOE4 is a gene variant
that increases amyloid,

137
00:07:01,608 --> 00:07:04,876
but you can inherit a copy of APOE4
from mom and dad

138
00:07:04,900 --> 00:07:07,291
and still never get Alzheimer's,

139
00:07:07,315 --> 00:07:09,428
which means that for most of us,

140
00:07:09,452 --> 00:07:13,292
our DNA alone does not determine
whether we get Alzheimer's.

141
00:07:13,984 --> 00:07:15,458
So what does?

142
00:07:15,482 --> 00:07:19,274
We can't do anything about getting older
or the genes we've inherited.

143
00:07:19,298 --> 00:07:22,295
So far, we haven't changed
our brain's destiny.

144
00:07:23,144 --> 00:07:24,609
What about sleep?

145
00:07:25,278 --> 00:07:29,360
In slow-wave deep sleep, our glial cells
rinse cerebral spinal fluid

146
00:07:29,384 --> 00:07:30,600
throughout our brains,

147
00:07:30,624 --> 00:07:34,196
clearing away metabolic waste
that accumulated in our synapses

148
00:07:34,220 --> 00:07:36,121
while we were awake.

149
00:07:36,145 --> 00:07:38,951
Deep sleep is like
a power cleanse for the brain.

150
00:07:39,646 --> 00:07:42,832
But what happens if you shortchange
yourself on sleep?

151
00:07:43,421 --> 00:07:44,953
Many scientists believe

152
00:07:44,977 --> 00:07:49,227
that poor sleep hygiene might actually
be a predictor of Alzheimer's.

153
00:07:49,613 --> 00:07:54,539
A single night of sleep deprivation
leads to an increase in amyloid beta.

154
00:07:55,410 --> 00:07:58,836
And amyloid accumulation
has been shown to disrupt sleep,

155
00:07:58,860 --> 00:08:01,347
which in turn causes
more amyloid to accumulate.

156
00:08:01,371 --> 00:08:03,847
And so now we have
this positive feedback loop

157
00:08:03,871 --> 00:08:06,744
that's going to accelerate
the tipping of that scale.

158
00:08:07,306 --> 00:08:08,729
What else?

159
00:08:08,753 --> 00:08:10,379
Cardiovascular health.

160
00:08:11,043 --> 00:08:14,788
High blood pressure, diabetes,
obesity, smoking, high cholesterol,

161
00:08:14,812 --> 00:08:18,948
have all been shown to increase our risk
of developing Alzheimer's.

162
00:08:18,972 --> 00:08:20,863
Some autopsy studies have shown

163
00:08:20,887 --> 00:08:23,559
that as many as 80 percent
of people with Alzheimer's

164
00:08:23,583 --> 00:08:26,345
also had cardiovascular disease.

165
00:08:26,369 --> 00:08:31,374
Aerobic exercise has been shown
in many studies to decrease amyloid beta

166
00:08:31,398 --> 00:08:33,128
in animal models of the disease.

167
00:08:33,619 --> 00:08:37,199
So a heart-healthy
Mediterranean lifestyle and diet

168
00:08:37,223 --> 00:08:39,877
can help to counter
the tipping of this scale.

169
00:08:40,697 --> 00:08:43,046
So there are many things we can do

170
00:08:43,070 --> 00:08:45,442
to prevent or delay
the onset of Alzheimer's.

171
00:08:45,466 --> 00:08:47,695
But let's say
you haven't done any of them.

172
00:08:48,211 --> 00:08:50,665
Let's say you're 65;

173
00:08:50,689 --> 00:08:54,355
there's Alzheimer's in your family,
so you've likely inherited a gene or two

174
00:08:54,379 --> 00:08:56,403
that tips your scale arm a bit;

175
00:08:56,427 --> 00:08:59,159
you've been burning the candle
at both ends for years;

176
00:08:59,183 --> 00:09:00,686
you love bacon;

177
00:09:00,710 --> 00:09:02,933
and you don't run unless
someone's chasing you.

178
00:09:02,957 --> 00:09:04,258
(Laughter)

179
00:09:04,282 --> 00:09:07,894
Let's imagine that your amyloid plaques
have reached that tipping point.

180
00:09:07,918 --> 00:09:09,966
Your scale arm has crashed to the floor.

181
00:09:09,990 --> 00:09:11,671
You've tripped the cascade,

182
00:09:11,695 --> 00:09:13,261
setting fire to the forest,

183
00:09:13,285 --> 00:09:16,383
causing inflammation, tangles,
and cell death.

184
00:09:17,137 --> 00:09:19,796
You should be symptomatic for Alzheimer's.

185
00:09:19,820 --> 00:09:23,136
You should be having trouble
finding words and keys

186
00:09:23,160 --> 00:09:26,306
and remembering what I said
at the beginning of this talk.

187
00:09:26,917 --> 00:09:28,631
But you might not be.

188
00:09:29,180 --> 00:09:31,658
There's one more thing you can do
to protect yourself

189
00:09:31,682 --> 00:09:34,268
from experiencing
the symptoms of Alzheimer's,

190
00:09:34,292 --> 00:09:38,783
even if you have the full-blown disease
pathology ablaze in your brain.

191
00:09:38,807 --> 00:09:42,714
It has to do with neural plasticity
and cognitive reserve.

192
00:09:43,261 --> 00:09:45,638
Remember, the experience
of having Alzheimer's

193
00:09:45,662 --> 00:09:48,868
is ultimately a result of losing synapses.

194
00:09:49,339 --> 00:09:52,716
The average brain has
over a hundred trillion synapses,

195
00:09:52,740 --> 00:09:55,453
which is fantastic;
we've got a lot to work with.

196
00:09:55,477 --> 00:09:57,146
And this isn't a static number.

197
00:09:57,170 --> 00:09:59,568
We gain and lose synapses all the time,

198
00:09:59,592 --> 00:10:02,395
through a process
called neural plasticity.

199
00:10:02,419 --> 00:10:04,491
Every time we learn something new,

200
00:10:04,515 --> 00:10:08,642
we are creating and strengthening
new neural connections,

201
00:10:08,666 --> 00:10:10,283
new synapses.

202
00:10:10,988 --> 00:10:12,563
In the Nun Study,

203
00:10:12,587 --> 00:10:17,480
678 nuns, all over the age of 75
when the study began,

204
00:10:17,504 --> 00:10:19,813
were followed for more than two decades.

205
00:10:19,837 --> 00:10:23,297
They were regularly given
physical checkups and cognitive tests,

206
00:10:23,321 --> 00:10:27,369
and when they died, their brains
were all donated for autopsy.

207
00:10:27,393 --> 00:10:31,768
In some of these brains, scientists
discovered something surprising.

208
00:10:31,792 --> 00:10:36,368
Despite the presence of plaques
and tangles and brain shrinkage --

209
00:10:36,392 --> 00:10:39,261
what appeared to be
unquestionable Alzheimer's --

210
00:10:39,285 --> 00:10:42,964
the nuns who had belonged
to these brains showed no signs

211
00:10:42,988 --> 00:10:45,555
of having the disease
while they were alive.

212
00:10:46,181 --> 00:10:47,630
How can this be?

213
00:10:48,009 --> 00:10:52,136
We think it's because these nuns
had a high level of cognitive reserve,

214
00:10:52,160 --> 00:10:56,083
which is a way of saying that they had
more functional synapses.

215
00:10:56,107 --> 00:10:58,681
People who have more years
of formal education,

216
00:10:58,705 --> 00:11:00,940
who have a high degree of literacy,

217
00:11:00,964 --> 00:11:04,543
who engage regularly
in mentally stimulating activities,

218
00:11:04,567 --> 00:11:07,048
all have more cognitive reserve.

219
00:11:07,072 --> 00:11:11,199
They have an abundance
and a redundancy in neural connections.

220
00:11:11,223 --> 00:11:13,903
So even if they have a disease
like Alzheimer's

221
00:11:13,927 --> 00:11:15,981
compromising some of their synapses,

222
00:11:16,005 --> 00:11:18,990
they've got many extra backup connections,

223
00:11:19,014 --> 00:11:22,349
and this buffers them from noticing
that anything is amiss.

224
00:11:22,977 --> 00:11:25,239
Let's imagine a simplified example.

225
00:11:25,263 --> 00:11:27,989
Let's say you only know one thing
about a subject.

226
00:11:28,013 --> 00:11:29,542
Let's say it's about me.

227
00:11:29,566 --> 00:11:31,872
You know that Lisa Genova
wrote "Still Alice,"

228
00:11:31,896 --> 00:11:34,332
and that's the only thing
you know about me.

229
00:11:34,356 --> 00:11:36,746
You have that single neural connection,

230
00:11:36,770 --> 00:11:38,716
that one synapse.

231
00:11:38,740 --> 00:11:40,901
Now imagine you have Alzheimer's.

232
00:11:40,925 --> 00:11:43,258
You have plaques and tangles
and inflammation

233
00:11:43,282 --> 00:11:46,017
and microglia devouring that synapse.

234
00:11:46,603 --> 00:11:50,833
Now when someone asks you,
"Hey, who wrote 'Still Alice?'"

235
00:11:50,857 --> 00:11:52,102
you can't remember,

236
00:11:52,126 --> 00:11:55,309
because that synapse
is either failing or gone.

237
00:11:55,333 --> 00:11:57,092
You've forgotten me forever.

238
00:11:57,760 --> 00:12:00,386
But what if you had learned more about me?

239
00:12:00,410 --> 00:12:02,499
Let's say you learned
four things about me.

240
00:12:02,523 --> 00:12:04,368
Now imagine you have Alzheimer's,

241
00:12:04,392 --> 00:12:07,387
and three of those synapses
are damaged or destroyed.

242
00:12:08,077 --> 00:12:10,538
You still have a way
to detour the wreckage.

243
00:12:10,562 --> 00:12:12,581
You can still remember my name.

244
00:12:13,283 --> 00:12:17,209
So we can be resilient
to the presence of Alzheimer's pathology

245
00:12:17,233 --> 00:12:20,336
through the recruitment
of yet-undamaged pathways.

246
00:12:20,360 --> 00:12:24,139
And we create these pathways,
this cognitive reserve,

247
00:12:24,163 --> 00:12:25,863
by learning new things.

248
00:12:26,455 --> 00:12:30,976
Ideally, we want these new things
to be as rich in meaning as possible,

249
00:12:31,000 --> 00:12:35,739
recruiting sight and sound
and associations and emotion.

250
00:12:36,398 --> 00:12:39,533
So this really doesn't mean
doing crossword puzzles.

251
00:12:39,557 --> 00:12:43,654
You don't want to simply retrieve
information you've already learned,

252
00:12:43,678 --> 00:12:47,021
because this is like traveling
down old, familiar streets,

253
00:12:47,045 --> 00:12:49,630
cruising neighborhoods you already know.

254
00:12:50,113 --> 00:12:52,947
You want to pave new neural roads.

255
00:12:52,971 --> 00:12:55,483
Building an Alzheimer's-resistant brain

256
00:12:55,507 --> 00:12:57,687
means learning to speak Italian,

257
00:12:57,711 --> 00:12:59,221
meeting new friends,

258
00:12:59,245 --> 00:13:00,412
reading a book,

259
00:13:00,436 --> 00:13:02,805
or listening to a great TED Talk.

260
00:13:03,283 --> 00:13:08,596
And if, despite all of this, you are
someday diagnosed with Alzheimer's,

261
00:13:08,620 --> 00:13:11,773
there are three lessons I've learned
from my grandmother

262
00:13:11,797 --> 00:13:15,534
and the dozens of people I've come to know
living with this disease.

263
00:13:16,115 --> 00:13:19,299
Diagnosis doesn't mean
you're dying tomorrow.

264
00:13:19,323 --> 00:13:21,045
Keep living.

265
00:13:21,069 --> 00:13:23,435
You won't lose your emotional memory.

266
00:13:23,459 --> 00:13:26,965
You'll still be able
to understand love and joy.

267
00:13:26,989 --> 00:13:29,992
You might not remember
what I said five minutes ago,

268
00:13:30,016 --> 00:13:32,301
but you'll remember how I made you feel.

269
00:13:32,944 --> 00:13:36,220
And you are more than what
you can remember.

270
00:13:36,244 --> 00:13:37,533
Thank you.

271
00:13:37,557 --> 00:13:42,880
(Applause)