1
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How many people here would like to live
to be at least 80 years old?

2
00:00:06,342 --> 00:00:07,956
Yeah.

3
00:00:07,956 --> 00:00:10,618
I think we all have
this hopeful expectation

4
00:00:10,618 --> 00:00:12,828
of living into old age.

5
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Let's project out into the future,

6
00:00:15,135 --> 00:00:16,718
to your future yous,

7
00:00:16,718 --> 00:00:19,595
and let's imagine that we're all 85.

8
00:00:19,595 --> 00:00:22,851
Now everyone look at two people.

9
00:00:22,851 --> 00:00:27,130
One of you probably has
Alzheimer's disease.

10
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Alright, alright.

11
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And maybe you're thinking, well,

12
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it won't be me.

13
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Then, okay, you are a caregiver.

14
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So in some way,

15
00:00:47,035 --> 00:00:50,933
this terrifying disease
is likely to affect us all.

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Part of the fear around Alzheimer's
stems from the sense

17
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that there's nothing we can do about it.

18
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Despite decades of research, we still
have no disease-modifying treatment

19
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and no cure.

20
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So if we're lucky enough
to live long enough,

21
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Alzheimer's appears to be
our brain's destiny.

22
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But maybe it doesn't have to be.

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What if I told you we could
change these statistics,

24
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literally change our brain's destiny,

25
00:01:17,688 --> 00:01:22,118
without relying on a cure
or advancements in medicine?

26
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Let's begin by looking at
what we currently understand

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about the neuroscience of Alzheimer's.

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Here's a picture
of two neurons connecting.

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The point of connection,
this space circled in red,

30
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is called the synapse.

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The synapse is where
neurotransmitters are released.

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This is where signals are transmitted,

33
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where communication happens.

34
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This is where we think,

35
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feel, see, hear, desire,

36
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and remember.

37
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And the synapse
is where Alzheimer's happens.

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Let's zoom in on the synapse

39
00:01:55,169 --> 00:01:58,918
and look at a cartoon representation
of what's going on.

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During the business
of communicating information,

41
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in addition to releasing neurotransmitters
like glutamate into the synapse,

42
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neurons also release a small peptide

43
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called amyloid beta.

44
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Normally, amyloid beta is cleared away
and metabolized by microglia,

45
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the janitor cells of our brains.

46
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While the molecular causes
of Alzheimer's are still debated,

47
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most neuroscientists believe
that the disease begins

48
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when amyloid beta begins to accumulate.

49
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Too much is released,
or not enough is cleared away,

50
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and the synapse begins
to pile up with amyloid beta.

51
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And when this happens, it binds to itself,

52
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forming sticky aggregates
called amyloid plaques.

53
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How many people here
are 40 years old or older?

54
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You're afraid to admit it now.

55
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This initial step into the disease,

56
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this presence of amyloid
plaques accumulating,

57
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can already be found in your brains.

58
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Now, the only way we could
be sure of this would be

59
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through a PET scan, because at this point,

60
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you are blissfully unaware.

61
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You're not showing any impairments
in memory, language, or cognition

62
00:03:08,049 --> 00:03:09,471
yet.

63
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We think it takes at least 15 to 20 years
of amyloid plaque accumulation

64
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before it reaches a tipping point,

65
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then triggering a molecular cascade

66
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that causes the clinical
symptoms of the disease.

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Prior to the tipping point,

68
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your lapses in memory
might include things like,

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"Why did I come in this room?"

70
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or "Oh, what's his name?"

71
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or "Where did I put my keys?"

72
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Yeah, now before you all
start freaking out again,

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because I know half of you

74
00:03:40,645 --> 00:03:42,978
did at least one of those
in the last 24 hours,

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these are all normal kinds of forgetting.

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In fact, I would argue that these examples

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might not even involve your memory,

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because you didn't pay attention

79
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to where you put your keys
in the first place.

80
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After the tipping point,

81
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the glitches in memory,
language, and cognition are different.

82
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Instead of eventually finding
your keys in your coat pocket,

83
00:04:03,612 --> 00:04:05,507
or on the table by the door,

84
00:04:05,507 --> 00:04:08,539
you find them in the refrigerator,

85
00:04:08,539 --> 00:04:10,366
or you find them and you think,

86
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"What are these for?"

87
00:04:12,672 --> 00:04:16,362
Okay, so what happens
when amyloid plaques

88
00:04:16,362 --> 00:04:18,217
accumulate to this tipping point?

89
00:04:18,217 --> 00:04:21,559
Our microglia janitor cells
become hyper-activated,

90
00:04:21,559 --> 00:04:25,716
releasing chemicals that cause
inflammation and cellular damage.

91
00:04:25,716 --> 00:04:28,196
We think they might actually
start clearing away

92
00:04:28,196 --> 00:04:30,620
the synapses themselves.

93
00:04:30,620 --> 00:04:33,650
A crucial neural transport protein
called tau becomes hyperphosphorylated

94
00:04:33,650 --> 00:04:37,478
and twists itself
into something called tangles

95
00:04:37,478 --> 00:04:40,443
which choke off the neurons
from the inside.

96
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By mid-stage Alzheimer's,
we have massive inflammation and tangles

97
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and all-out war at the synapse

98
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and cell death.

99
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So if you are a scientist
trying to cure this disease,

100
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at what point would you ideally
want to intervene?

101
00:04:55,174 --> 00:04:59,062
Many scientists are betting big
on the simplest solution:

102
00:04:59,062 --> 00:05:02,852
keep amyloid plaques
from reaching that tipping point,

103
00:05:02,852 --> 00:05:06,282
which means that drug discovery
is largely focused on developing

104
00:05:06,282 --> 00:05:08,279
a compound that will prevent,

105
00:05:08,279 --> 00:05:13,019
eliminate, or reduce
amyloid plaque accumulation.

106
00:05:13,019 --> 00:05:14,805
And so the cure for Alzheimer's

107
00:05:14,805 --> 00:05:18,072
will likely be a preventative medicine.

108
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We're going to have to take this pill
before we reach that tipping point,

109
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before the cascade is triggered,

110
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before we start leaving
our keys in the refrigerator.

111
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We think this is why, to date, these kinds
of drugs have failed in clinical trials,

112
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not because the science wasn't sound,

113
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but because the people in these trials

114
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were already symptomatic.

115
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It was too late.

116
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Think of amyloid plaques as a lit match.

117
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At the tipping point, the match
sets fire to the forest.

118
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Once the forest is ablaze,

119
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it doesn't do any good
to blow out the match.

120
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You have to blow out the match
before the forest catches fire.

121
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Even before scientists sort this out,

122
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this information is actually
really good news for us,

123
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because it turns out that the way
we live can influence

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the accumulation of amyloid plaques.

125
00:06:06,431 --> 00:06:08,031
And so there are things we can do

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to keep us from reaching
that tipping point.

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Let's picture your risk of Alzheimer's

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as a see-saw scale.

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We're going to pile
risk factors on one arm,

130
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and when that arm hits the floor,
you are symptomatic

131
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and diagnosed with Alzheimer's.

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Let's imagine you're 50 years old.

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You're not a spring chicken anymore,

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so you've accumulated
some amyloid plaques with age.

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You're scale is tipped a little bit.

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Now let's look at your DNA.

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We've all inherited our genes
from our moms and our dads.

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Some of these genes will increase our risk

139
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and some will decrease it.

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If you're like Alice in "Still Alice,"

141
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you've inherited a rare genetic mutation

142
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that cranks out amyloid beta,

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and this alone will tip
your scale arm to the ground.

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00:06:52,579 --> 00:06:56,433
But for most of us, the genes
we inherit will only tip the arm a bit.

145
00:06:56,433 --> 00:06:59,042
For example, APOE4 is a gene variant

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that increases amyloid,

147
00:07:01,270 --> 00:07:04,900
but you can inherit a copy of APOE4
from mom and dad

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00:07:04,900 --> 00:07:07,315
and still never get Alzheimer's,

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00:07:07,315 --> 00:07:10,346
which means that for most of us,

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our DNA alone does not determine
whether we get Alzheimer's.

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So what does?

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We can't do anything about getting older

153
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or the genes we've inherited.

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So far, we haven't changed
our brain's destiny.

155
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What about sleep?

156
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In slow-wave deep sleep,
our glial cells

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rinse cerebral spinal fluid
throughout our brains

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clearing away metabolic waste
that accumulated in our synapses

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while we were awake.

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Deep sleep is like
a power cleanse for the brain.

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But what happens if you short-change
yourself on sleep?

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Many scientists believe
that poor sleep hygiene

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might actually be
a predictor of Alzheimer's.

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A single night of sleep deprivation
leads to an increase in amyloid beta.

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And amyloid accumulation
has been shown to disrupt sleep,

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which in turn causes
more amyloid to accumulate.

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00:08:01,506 --> 00:08:04,005
And so now we have
this positive feedback loop

168
00:08:04,005 --> 00:08:07,482
that's going to accelerate
the tipping of that scale.

169
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What else?

170
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Cardiovascular health.

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High blood pressure, diabetes,
obesity, smoking, high cholesterol,

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00:08:14,837 --> 00:08:18,830
have all been shown to increase
our risk of developing Alzheimer's.

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Some autopsy studies have shown
that as many as 80 percent

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of people with Alzheimer's
also had cardiovascular disease.

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Aerobic exercise has been shown
in many studies

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to decrease amyloid beta

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in animal models of the disease.

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So a heart-healthy Mediterranean
lifestyle and diet

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can help to counter
the tipping of this scale.

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Okay, so there are many things
we can do to prevent

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or delay the onset of Alzheimer's,

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but let's say you haven't
done any of them.

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Let's say you're 65,

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00:08:50,631 --> 00:08:54,215
there's Alzheimer's in your family,
so you've likely inherited a gene or two

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that tips your scale arm a bit,

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00:08:56,303 --> 00:08:59,183
you've been burning the candle
at both ends for years,

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00:08:59,183 --> 00:09:00,710
you love bacon,

188
00:09:00,710 --> 00:09:04,063
and you don't run unless
someone's chasing you.

189
00:09:04,063 --> 00:09:07,918
Let's imagine that your amyloid plaques
have reached that tipping point.

190
00:09:07,918 --> 00:09:09,990
Your scale arm has crashed to the floor.

191
00:09:09,990 --> 00:09:11,695
You've tripped the cascade,

192
00:09:11,695 --> 00:09:13,285
setting fire to the forest,

193
00:09:13,285 --> 00:09:16,619
causing inflammation, tangles,
and cell death.

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00:09:16,619 --> 00:09:19,820
You should be symptomatic for Alzheimer's.

195
00:09:19,820 --> 00:09:23,160
You should be having trouble
finding words and keys

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00:09:23,160 --> 00:09:26,917
and remember what I said
at the beginning of this talk.

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But you might not be.

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There's one more thing you can do
to protect yourself

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00:09:31,765 --> 00:09:33,984
from experiencing
the symptoms of Alzheimer's

200
00:09:33,984 --> 00:09:38,326
even if you have the full-blown disease
pathology ablaze in your brain.

201
00:09:38,326 --> 00:09:42,979
It has to do with neural plasticity
and cognitive reserve.

202
00:09:42,979 --> 00:09:45,413
Remember, the experience
of having Alzheimer's

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00:09:45,413 --> 00:09:49,339
is ultimately a result of losing synapses.

204
00:09:49,339 --> 00:09:52,835
The average brain has
over a hundred trillion synapses,

205
00:09:52,835 --> 00:09:55,318
which is fantastic. We've got
a lot to work with.

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00:09:55,318 --> 00:09:57,170
And this isn't a static number.

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00:09:57,170 --> 00:10:00,514
We gain and lose synapses
all the time through a process

208
00:10:00,514 --> 00:10:02,215
called neural plasticity.

209
00:10:02,215 --> 00:10:04,515
Every time we learn something new,

210
00:10:04,515 --> 00:10:08,332
we are creating and strengthening
new neural connections,

211
00:10:08,332 --> 00:10:10,996
new synapses.

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00:10:10,996 --> 00:10:13,397
In the nun study,

213
00:10:13,397 --> 00:10:13,647
678 nuns,

214
00:10:13,647 --> 00:10:17,389
all over the age of 75
when the study began,

215
00:10:17,389 --> 00:10:19,915
were followed for more than two decades.

216
00:10:19,915 --> 00:10:23,321
They were regularly given
physical checkups and cognitive tests

217
00:10:23,321 --> 00:10:27,053
and when they died, their brains
were all donated for autopsy.

218
00:10:27,053 --> 00:10:31,792
In some of these brains, scientists
discovered something surprising.

219
00:10:31,792 --> 00:10:36,248
Despite the presence of plaques
and tangles and brain shrinkage,

220
00:10:36,248 --> 00:10:39,285
what appeared to be
unquestionable Alzheimer's,

221
00:10:39,285 --> 00:10:41,793
the nuns who had belonged to these brains

222
00:10:41,793 --> 00:10:46,292
showed no signs of having the disease
while they were alive.

223
00:10:46,292 --> 00:10:48,176
How can this be?

224
00:10:48,176 --> 00:10:51,972
We think it is because these nuns
had a high level of cognitive reserve,

225
00:10:51,972 --> 00:10:56,107
which is a way of saying that they had
more functional synapses.

226
00:10:56,107 --> 00:10:58,551
People who have more years
of formal education,

227
00:10:58,551 --> 00:11:00,964
who have a high degree of literacy,

228
00:11:00,964 --> 00:11:04,567
who engage regularly
in mentally stimulating activities,

229
00:11:04,567 --> 00:11:07,072
all have more cognitive reserve.

230
00:11:07,072 --> 00:11:11,107
They have an abundance
and a redundancy in neural connections.

231
00:11:11,107 --> 00:11:13,621
So even if they have a disease
like Alzheimer's

232
00:11:13,621 --> 00:11:16,005
compromising some of their synapses,

233
00:11:16,005 --> 00:11:19,329
they've got many extra backup connections,

234
00:11:19,329 --> 00:11:23,041
and this buffers them from noticing
that anything is amiss.

235
00:11:23,041 --> 00:11:25,427
Let's imagine a simplified example.

236
00:11:25,427 --> 00:11:28,176
Let's say you only know one thing
about a subject.

237
00:11:28,176 --> 00:11:29,728
Let's say it's about me.

238
00:11:29,728 --> 00:11:32,057
You know that Lisa Genova
wrote "Still Alice,"

239
00:11:32,057 --> 00:11:34,597
and that's the only thing
you know about me.

240
00:11:34,597 --> 00:11:36,916
You have that single neural connection,

241
00:11:36,916 --> 00:11:38,885
that one synapse.

242
00:11:38,885 --> 00:11:40,748
Now imagine you have Alzheimer's.

243
00:11:40,748 --> 00:11:43,445
You have plaques and tangles
and inflammation

244
00:11:43,445 --> 00:11:46,627
and microglia devouring that synapse.

245
00:11:46,627 --> 00:11:50,087
Now, when someone asks you,
"Hey, who wrote 'Still Alice?'"

246
00:11:50,087 --> 00:11:55,333
you can't remember, because
that synapse is either failing or gone.

247
00:11:55,333 --> 00:11:57,760
You've forgotten me forever.

248
00:11:57,760 --> 00:12:00,239
But what if you had learned more about me?

249
00:12:00,239 --> 00:12:02,533
Let's say you learned
four things about me.

250
00:12:02,533 --> 00:12:05,290
Now imagine you have Alzheimer's,

251
00:12:05,290 --> 00:12:07,983
and three of those synapses
are damaged or destroyed.

252
00:12:07,983 --> 00:12:10,733
You still have a way
to detour the wreckage.

253
00:12:10,733 --> 00:12:13,394
You can still remember my name.

254
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So we can be resilient
to the presence of Alzheimer's pathology

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through the recruitment of
yet undamaged pathways,

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and we create these pathways,

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this cognitive reserve,

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by learning new things.

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Now ideally we want these new things
to be as rich in meaning as possible,

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recruiting sight and sound
and associations and emotion.

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So this really doesn't mean
doing crossword puzzles.

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You don't want to simply retrieve
information you've already learned,

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because this is like traveling
down old, familiar streets,

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cruising neighborhoods you already know.

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You want to pave new neural roads.

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Building an Alzheimer's-resistant brain

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means learning to speak Italian,

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meeting new friends,

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reading a book,

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or listening to a great TEDTalk.

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And if despite all of this, you are
someday diagnosed with Alzheimer's,

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there are three lessons I've learned
from my grandmother

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and the dozens of people I've come
to know living with this disease.

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Diagnosis doesn't mean
you're dying tomorrow.

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Keep living.

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You won't lose your emotional memory.

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You'll still be able to understand
love and joy.

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You might not remember what I said
five minutes ago,

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but you'll remember
how I made you feel.

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And you are more than what
you can remember.

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Thank you.

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(Applause)