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

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Yeah.

3
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I think we all have
this hopeful expectation

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of living into old age.

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Let's project out into the future,

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to your future yous,

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and let's imagine that we're all 85.

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Now everyone look at two people.

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One of you probably has
Alzheimer's disease.

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Alright, alright.

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And maybe you're thinking, well,

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it won't be me.

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Then, okay, you are a caregiver.

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So in some way,

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this terrifying disease
is likely to affect us all.

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

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that there's nothing we can do about it.

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

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and no cure.

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

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

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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,

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literally change our brain's destiny,

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without relying on a cure
or advancements in medicine?

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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,

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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,

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where communication happens.

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This is where we think,

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feel, see, hear, desire,

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and remember.

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And the synapse
is where Alzheimer's happens.

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Let's zoom in on the synapse

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and look at a cartoon representation
of what's going on.

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During the business
of communicating information,

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in addition to releasing neurotransmitters
like glutamate into the synapse,

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neurons also release a small peptide

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called amyloid beta.

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

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the janitor cells of our brains.

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

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most neuroscientists believe
that the disease begins

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when amyloid beta begins to accumulate.

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

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and the synapse begins
to pile up with amyloid beta.

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And when this happens, it binds to itself,

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forming sticky aggregates
called amyloid plaques.

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How many people here
are 40 years old or older?

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You're afraid to admit it now.

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This initial step into the disease,

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this presence of amyloid
plaques accumulating,

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can already be found in your brains.

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

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through a PET scan, because at this point,

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you are blissfully unaware.

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

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yet.

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

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before it reaches a tipping point,

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then triggering a molecular cascade

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that causes the clinical
symptoms of the disease.

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Prior to the tipping point,

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your lapses in memory
might include things like,

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"Why did I come in this room?"

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or "Oh, what's his name?"

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or "Where did I put my keys?"

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Yeah, now before you all
start freaking out again,

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because I know half of you

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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

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to where you put your keys
in the first place.

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After the tipping point,

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

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Instead of eventually finding
your keys in your coat pocket,

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or on the table by the door,

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you find them in the refrigerator,

85
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or you find them and you think,

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"What are these for?"

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Okay, so what happens
when amyloid plaques

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accumulate to this tipping point?

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Our microglia janitor cells
become hyper-activated,

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releasing chemicals that cause
inflammation and cellular damage.

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We think they might actually
start clearing away

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the synapses themselves.

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A crucial neural transport protein
called tau becomes hyperphosphorylated

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and twists itself
into something called tangles

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which choke off the neurons
from the inside.

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

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and all-out war at the synapse

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and cell death.

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

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at what point would you ideally
want to intervene?

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Many scientists are betting big
on the simplest solution:

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keep amyloid plaques
from reaching that tipping point,

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which means that drug discovery
is largely focused on developing

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a compound that will prevent,

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eliminate, or reduce
amyloid plaque accumulation.

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And so the cure for Alzheimer's

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will likely be a preventative medicine.

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

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before the cascade is triggered,

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before we start leaving
our keys in the refrigerator.

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

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not because the science wasn't sound,

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but because the people in these trials

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were already symptomatic.

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It was too late.

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Think of amyloid plaques as a lit match.

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

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Once the forest is ablaze,

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

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

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Even before scientists sort this out,

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this information is actually
really good news for us,

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because it turns out that the way
we live can influence

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the accumulation of amyloid plaques.

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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,

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and when that arm hits the floor,
you are symptomatic

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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

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and some will decrease it.

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

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you've inherited a rare genetic mutation

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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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But for most of us, the genes
we inherit will only tip the arm a bit.

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For example, APOE4 is a gene variant

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that increases amyloid,

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but you can inherit a copy of APOE4
from mom and dad

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and still never get Alzheimer's,

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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

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or the genes we've inherited.

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

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What about sleep?

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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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And so now we have
this positive feedback loop

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that's going to accelerate
the tipping of that scale.

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What else?

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Cardiovascular health.

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

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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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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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you've been burning the candle
at both ends for years,

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you love bacon,

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and you don't run unless
someone's chasing you.

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Let's imagine that your amyloid plaques
have reached that tipping point.

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Your scale arm has crashed to the floor.

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You've tripped the cascade,

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setting fire to the forest,

193
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causing inflammation, tangles,
and cell death.

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You should be symptomatic for Alzheimer's.

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You should be having trouble
finding words and keys

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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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from experiencing
the symptoms of Alzheimer's

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even if you have the full-blown disease
pathology ablaze in your brain.

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It has to do with neural plasticity
and cognitive reserve.

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Remember, the experience
of having Alzheimer's

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is ultimately a result of losing synapses.

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The average brain has
over a hundred trillion synapses,

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which is fantastic. We've got
a lot to work with.

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And this isn't a static number.

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We gain and lose synapses
all the time through a process

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called neural plasticity.

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99:59:59,999 --> 99:59:59,999
Every time we learn something new,

210
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we are creating and strengthening
new neural connections,

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new synapses.

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99:59:59,999 --> 99:59:59,999
In the nun study,

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678 nuns,

214
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all over the age of 75
when the study began,

215
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were followed for more than two decades.

216
99:59:59,999 --> 99:59:59,999
They were regularly given
physical checkups and cognitive tests

217
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and when they died, their brains
were all donated for autopsy.

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99:59:59,999 --> 99:59:59,999
In some of these brains, scientists
discovered something surprising.

219
99:59:59,999 --> 99:59:59,999
Despite the presence of plaques
and tangles and brain shrinkage,

220
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what appeared to be
unquestionable Alzheimer's,

221
99:59:59,999 --> 99:59:59,999
the nuns who had belonged to these brains

222
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showed no signs of having the disease
while they were alive.

223
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How can this be?

224
99:59:59,999 --> 99:59:59,999
We think it is because these nuns
had a high level of cognitive reserve,

225
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which is a way of saying that they had
more functional synapses.

226
99:59:59,999 --> 99:59:59,999
People who have more years
of formal education,

227
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who have a high degree of literacy,

228
99:59:59,999 --> 99:59:59,999
who engage regularly
in mentally stimulating activities,

229
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all have more cognitive reserve.

230
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They have an abundance
and a redundancy in neural connections.

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So even if they have a disease
like Alzheimer's

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compromising some of their synapses,

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they've got many extra backup connections,

234
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and this buffers them from noticing
that anything is amiss.

235
99:59:59,999 --> 99:59:59,999
Let's imagine a simplified example.

236
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Let's say you only know one thing
about a subject.

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Let's say it's about me.

238
99:59:59,999 --> 99:59:59,999
You know that Lisa Genova
wrote "Still Alice,"

239
99:59:59,999 --> 99:59:59,999
and that's the only thing
you know about me.

240
99:59:59,999 --> 99:59:59,999
You have that single neural connection,

241
99:59:59,999 --> 99:59:59,999
that one synapse.

242
99:59:59,999 --> 99:59:59,999
Now imagine you have Alzheimer's.

243
99:59:59,999 --> 99:59:59,999
You have plaques and tangles
and inflammation

244
99:59:59,999 --> 99:59:59,999
and microglia devouring that synapse.

245
99:59:59,999 --> 99:59:59,999
Now, when someone asks you,
"Hey, who wrote 'Still Alice?'"

246
99:59:59,999 --> 99:59:59,999
you can't remember, because
that synapse is either failing or gone.

247
99:59:59,999 --> 99:59:59,999
You've forgotten me forever.

248
99:59:59,999 --> 99:59:59,999
But what if you had learned more about me?

249
99:59:59,999 --> 99:59:59,999
Let's say you learned
four things about me.

250
99:59:59,999 --> 99:59:59,999
Now imagine you have Alzheimer's,

251
99:59:59,999 --> 99:59:59,999
and three of those synapses
are damaged or destroyed.

252
99:59:59,999 --> 99:59:59,999
You still have a way
to detour the wreckage.

253
99:59:59,999 --> 99:59:59,999
You can still remember my name.

254
99:59:59,999 --> 99:59:59,999
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)