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ABBY NOYCE: OK so we're going to talk about Alzheimer's disease.
Who here knows somebody who has or had Alzheimer's disease?
Anyone with family members?
No.
[BACKGROUND CONVERSATION]
Yeah, I'm lucky nobody in my family has it.
Anyway, so Alzheimer's disease is
part of a group of mental disorders known as dementias.
So dementias are a group of disorders,
diseases that are characterized by cognitive and behavioral
deficits.
So people's ability to think, remember, learn as well as they
used to declines.
This also is depending on which dementia we're discussing,
people's ability, for example, to take care of themselves,
to generally participate in their daily life declines.
Dementias are usually characterized by gradual onset.
So they start off with just a little bit of decline
and get worse over time.
They're chronic.
They're permanent.
This isn't something that you have and then get rid of.
Dementias are lifelong once you develop one.
In the clinical world, you make this distinction
between dementias which are these slow onset
chronic disorders and what are called deliriums.
So a delirium is acute.
It happens it's a quick change in cognitive ability.
Working with an older adult population,
you'll usually see delirium brought on by sometimes
by trauma, sometimes by a medication or a medication
interaction.
And all of these are things that cause older adults to end up
in the ER for some reason.
Somebody looks up and says, Grandma is acting weird.
Today something changed.
Take her, put Grandma in the car,
bring her to the emergency room.
First thing the ER doc says, is have Grandma's
medications change recently?
This is a big cause of a lot of short term
changes in older adults.
But dementias are different.
Dementias are usually caused by a bunch of things.
They can be caused by a progressive disease.
They can be caused by trauma.
They can be caused by a stroke.
And overall, different categories of these
affect about 4 million people in this country.
And that's almost all people over age 65.
AUDIENCE: What could be a trauma?
ABBY NOYCE: Trauma can be like a head injury or a stroke,
something that's kind of--
it's not so much a disease as something
has caused sudden death of some sort to cell in brain.
So Alzheimer's is a particular subset of dementia.
It's by far the most common one.
It was first described in 1907 Alois Alzheimer.
He was talking about a patient he'd
been working with for about six years at that point who
had a strange form of senile dementia.
And it's been known kind of casually
for a long time and more specifically more
recently that as people get older,
in general just in normal aging, your cognitive abilities
decline.
Older adults do poorer on a lot of memory tasks.
They're slower at a lot of reflex reaction time tasks.
In general, your cognitive abilities
slow down as people pass into their 50s, 60s, and beyond.
Alzheimer's is different.
It's more than anything, it's these same deficits
taken to an extreme.
And we'll talk a little bit about exactly what kinds
of changes you'll see in patients who have Alzheimer's.
Alzheimer's accounts for, depending
on whose estimate you ask, between 50% and 70% of all
dementias.
Because it correlates with lifespan
so well as people get older, your chances of getting
Alzheimer's increase, it's more common in countries
with longer lifespans.
So it's much more common in places like the US and Western
Europe than it is, for example, in like central Africa
just because we've got so many more adults who make it
into their 60s, 70s, 80s--
these periods where the incidence starts going way up.
All right, so how do you diagnose this?
So in order to get a definitive diagnosis
of Alzheimer's disease, this can only be done by autopsy.
But there's a bunch of criteria for making what's
called a clinical diagnosis-- a diagnosis
you can make while people are still alive
and say that you have Alzheimer's disease.
Why would you want to do this?
Why isn't it just good enough to say
you have some kind of dementia?
Well, one of the biggest reasons is
that the progression of different forms of dementia
is different.
So the time span that you are likely to have,
how fast the decline is likely to be
varies across different kinds of dimensions.
And being able to say which one someone has helps them
and their families kind of figure out what's going on,
what happens with this.
And in a clinical care setting, that's really important.
So the clinical criteria for Alzheimer's disease, and these
are kind of in flux.
But this is the American Psychological Association's
current round of diagnostic criteria.
And so to be diagnosed with Alzheimer's disease,
patients have to have multiple cognitive deficits.
They have to have memory impairment, which
is kind of the classic thing that everybody knows about
for Alzheimer's disease.
Alzheimer's disease, if you lose your memory,
you lose your ability to learn new information in particular.
Patients also have to have at least one
of the second group of cognitive deficits.
So remember aphasia is a group of disorders in which people
have a hard time with language, with understanding or producing
language.
Apraxia refers to a difficulty in making
smooth movements and motor coordination and control.
Agnosia-- go back a couple of weeks the agnosias are
our class of disorders which people have difficulty
recognizing visually presented objects and describing
or interacting with visually presented stimuli in various
ways--
or difficulties in executive function.
What kinds of activities is executive function refer to?
That's stuff like goal directed behavior,
planning cause and effect reasoning-- all of this
comes under this executive control heading.
And so you also see patients who have difficulty with this.
One of classic examples of this is--
there's some classic research working with babies,
like six-month-old babies where you show them
an object like a brightly colored little puppet
or something-- something that the kid would be
interested in and attracted to.
And you show the kid this.
Then they'll reach and then you put it into a box.
And they'll reach for the box that they
saw you put the puppet in.
And even if you then show the experimenter picking up
the thing and moving it to a different box
so there's like two boxes in front of the kid,
they'll keep reaching towards the original one, the one
that they saw go into first.
They don't seem to have the ability
to take the information about how the thing moved from place
one to place two and translate that
into a change in how they want to direct their motor
abilities.
They don't have the ability to kind of take
the reach for this box instruction
and transform it into a reach for that box over there
because the doll got moved instruction.
So little six-month-old babies make this mistake.
Patients with Alzheimer's will also make this mistake.
So patients with moderately advanced Alzheimer's will
make similar errors in--
probably not in brightly colored puppets but in a look for this,
see it move, and then have to transition your search
tasks to a new area.
They seem to have a hard time with it.
So that's an example of an executive control function
that's hindered, that's impaired in patients with Alzheimer's.
The other big criteria for anything like this
is that the way the DSM, the Diagnostic and Statistical
Manual, works is that in order to qualify
as having a disorder of any kind,
you've got to have impairment.
If you are finding that your memory is declining
and yet it is not messing up your daily life at all,
DSM will say you don't have a disorder.
You are working just fine.
You are not having a disorder.
So one of these criteria is a impairment
in function compared to the previous level of function.
So this is going to vary for different people
depending on how high their cognitive abilities were
before the onset of symptoms.
And the other requirement is that this is, like we said,
a gradual impairment.
This is not an acute sudden change in cognitive ability.
It's gradual, and it's progressive.
It gets worse over time.
So what does this progressiveness look like?
So most people break Alzheimer's into four main stages.
The first of which is what's called pre-dementia.
And in pre-dementia stage, most people
aren't diagnosed at this stage.
It's hard to tell the difference between cognitive decline
that's due to Alzheimer's disease
from what kind of your normal aging cognitive
decline that you're going to see in just about all adults
in their 60s and 70s.
But on the other hand, if you have people take,
for example, an IQ test every year starting at 65 on.
And when they're 80 they become diagnosed with Alzheimer's, you
can go back and look at their older tests.
And you can see evidence that there
was cognitive decline over the preceding five to seven years.
But it's not strong enough for it to really
be diagnosed as being a dementia of any kind.
So the next stage after the dementia
is what's called early dementia.
And this is usually when it gets noticed,
when it gets diagnosed.
You'll see that people's impairments for memory
and for learning new information are severe enough
that they'll go, they'll talk to their doctor.
They'll say, hey, I'm concerned about this.
And they're specifically bad about it
learning new information.
Childhood memories aren't impaired at this point.
Semantic knowledge, knowledge about the world
is not usually impaired.
This is the where did I put my keys
stage of Alzheimer's disease.
It's a new piece of information.
It's something from earlier today.
But it's just not there.
They can't pull this up
Next step is moderate dementia.
And at this stage, this is where you start seeing severe speech
and language impairment.
People can't pull out the knowledge about which words.
They want to use their vocabulary effectively
shrinks a lot more obscure words they just can't access anymore.
You see deterioration in motor control.
People have a hard time making smooth, coordinated movements.
People have serious impairment.
They start losing long term memory.
They start not being able to remember things
from when they were young.
They start not being able to remember facts about the world.
They start not recognizing family members, which
is kind of another classic Alzheimer's symptom
that people have a hard time dealing with.
This is the stage where usually people
start having a really hard time taking care of themselves.
Usually in that early dementia state,
you'll see individuals with Alzheimer's usually moving in
with a family member.
They're pretty much OK.
They can get around.
They can handle their stuff.
But often, family doesn't want them to live alone.
And in this modern dementia state,
that starts being really hard all around.
These are patients who are having
a hard time, for example, cooking and feeding themselves.
They might have start having a hard time tying their shoes.
They might say they're having a hard time taking a shower.
All of these are things which the people who they're living
with have to help them with.
So Alzheimer's is probably the biggest reason
for adults to be in a caregiver relationship with another adult
not counting like raising children.
But when you find people taking care of a sibling or a parent
or grandparent, it's usually due to what some kind of dementia.
The other thing that tends to happen in Alzheimer's
that's really distressing for family members
is that in this moderate stage dementia
that you start seeing affective changes.
You start seeing mood and personality changes
in these patients.
So people will start to become aggressive, angry, loud,
violent towards family members.
They'll push, they'll shove, they'll holler.
They'll say things that are completely inappropriate.
And as you might imagine, for somebody
who's giving up like all of their free time
and a good chunk of their general sanity in the world
to take care of this family member,
this can be really distressing all around.
So it's usually in this moderate stage
that you see families really considering moving somebody
with Alzheimer's from live-in caregiver family situation
into an assisted living sort of nursing home situation,
because the stress and the distress
of handling all of this just being
too much for ordinary people.
And then it progresses into what's
called advanced dementia.
And at this point, all of this just kind of gets worse.
Patients lose motor coordination and muscle tone,
eventually to the point where they are bedridden.
They usually need help feeding themselves.
They usually need help with all kinds of personal care tasks--
bathing, going to the bathroom, all of this.
They often lose pretty much all linguistic ability
at this point.
And eventually, these patients just lose physical condition
to the extent that any old infection that comes along
will take them out.
And that's usually what people actually die from who have
Alzheimer's.
It's not the disease itself.
It's that the disease leads to this deterioration that
then makes it makes them much more vulnerable
to other kinds of infections.
How long does this take?
Remember it's usually diagnosed that early dementia phase when
you first start seeing significant impairment
in learning and memory.
The mean time for survival after diagnosis is about seven years.
So that's the arithmetical average-- add up all the times
and divides them.
And very few patients, like 3% of patients
alive longer than 14 years after diagnosis.
So this isn't like immediate.
But it's a reasonably quick decline, fade,
death kind of story.
So as you might imagine, lots of people
were trying to figure out what exactly is going on
with Alzheimer's disease.
So what we've known for a while is that there's, macro scale,
pretty substantial differences between normal patients
brains' and the brains of patients with Alzheimer's.
The biggest thing that happens is
that in the temporal and frontal lobes,
you get a lot of cerebral cortex cell death.
Neurons, for one reason or another,
retreat from their synapses with other neurons
and eventually die.
And so what you'll see is that these brains just
have a lot less volume than they do in other--
so here's a normal patient.
And here's somebody with Alzheimer's disease.
And so you can see the way both the cortex
and all of these subcortical structures have shrunk.
You can see that the ventricle-- which
are the fluid filled spaces that are normally
inside your brain-- have enlarged.
Again, that's the brain itself is taking up less space.
So the cerebral spinal fluid spaces expand.
The hippocampus-- which should be this fit right in here where
it's folded around--
in a normal patient that would be all the way out to here.
So it's dramatically smaller.
This kind of macro scale, hey look, a lot of cells are dying.
You might imagine, OK, a lot of cells are dying.
It's no wonder that we're seeing this kind of serious cognitive
deficits.
So what's happening on a smaller scale?
Why are cells dying?
So there's two really characteristic changes
that happen at a cellular level in patients
who have Alzheimer's disease.
One of them is what's called these senile plaques,
these beta amyloid plaques.
So what happens is that amyloid precursor protein--
so this is a neuron.
Here is the cell membrane, here's the interior.
Amyoloid precursor protein is a transmembrane protein.
So it has parts that stick out both into the cell
and out into the extracellular fluid.
We're not entirely sure what it does.
It seems to be important in helping neurons
to grow and to repair themselves after any kind of damage that
might happen to them.
But what happens is that enzymes like
there's one called presenilin.
There's another one who I didn't write down, that was dumb.
But there's a couple of different kinds of enzymes
that, in Alzheimer's patients, seem to go a little bit out
of control.
So they come along, they break up this amyloid precursor
protein into several pieces.
And the piece that's relevant is this bit
that's right here sticking out along the transmembrane part
of it.
This part is called beta-amyloid.
And these beta-amyloid fragments,
when the proteins get snipped up by these enzymes,
float out here in the extracellular fluid.
And they all clump together.
They form these really characteristic senile plaques
or beta-amyloid plaques.
Here's an actual histological slide photo, micrograph.
So you can see in here and here and there, all of these
are places where you've got one of those senile plaques
going on where outside of the cell bodies
there are just all of these bits of beta-amyloid clumped up
on top of each other.
And one theory about what causes the decline
we see in Alzheimer's disease is that these senile
plaques all glom up on top, causing dysfunction
of cellular operation.
But we'll come back to that.
Questions?
Beta-amyloid plaques?
The other big neurological change that you see
is what's called neurofibrillary tangles.
Plaques and tangles, you guys might
have heard about these when you're
reading about Alzheimer's or seeing it discussed.
It's pretty well established at this point.
So what happens here is that these proteins
are part of the cytoskeleton of the neurons.
So you guys probably remember from learning
about cells in bio that cells have a cytoskeleton, which
does a couple of things.
It gives structure to the cell, it helps hold its shape.
But there's also a particular part of the cytoskeleton called
microtubules.
And microtubules act kind of like train
tracks going out to different parts of the cell.
They're involved in transporting proteins and vesicles
of neurotransmitter and other things
that the cell needs to move from one region to another,
it moves along these microtubules.
And one of the things that's involved
in keeping these microtubules stable is these tau proteins.
So diagram moment, so here's our neuron's axon.
And it's got lots of microtubules reaching down,
which are how the cell brings things from its nucleus
out to the axon tips.
And normally, these tau proteins have a phosphate group on them,
they're phosphorylated.
And at that point, the presence of a phosphate group
causes them to fold in such a shape
that they stabilize the microtubule.
They help hold it all together.
And what happens in patients with Alzheimer's disease
is that these tau proteins that should
be holding the microtubule together
become hyper-phosphorylated.
They get extra phosphate groups stuck onto them--
--That makes them unstable--
--which makes them unstable.
It causes them to change shape because proteins
are made up of amino acids.
and they want to fold up in such a manner
that the electric charges are all attracted and pushing apart
in the right way.
And so as you start adding phosphate groups onto them,
we talked about how phospholating receptors--
we talked two weeks ago about this--
causes them to change their behavior.
Again, it's a subtle change in shape that makes this happen.
So in this case when you stick to any phosphate groups
on a tau protein, it shifts.
It no longer manages to hold the microtubule together.
And so what happens is that this microtubule
starts to fall apart.
And the tau proteins, again, all clump together
and wrap around each other in these neurofibrillary tangles.
AUDIENCE: Can you go back one?
ABBY NOYCE: Maybe, yes.
AUDIENCE: So the two cellular level
sequences that we looked at, are these causes of the cell
deaths?
ABBY NOYCE: Nobody is entirely sure how that works.
There's hypotheses that say that these are
the causes of the cell deaths.
What we know is that they're distinct.
They happen in normal aging too, but they happen much more
in Alzheimer's patients and in different parts of the brain.
And so it's traditionally looking
at these particular cellular level
changes has been how that definitive Alzheimer's
diagnosis is made.
You say, OK, you've got all the clinical symptoms.
And after somebody dies, you do an autopsy.
You take a slice of their brain, and you look at it
under a microscope for the tangles and for the plaques.
They're starting to be some better
ways of doing this and some better ways
of on non-autopsy required diagnoses.
But so we've got--
AUDIENCE: Does that mean Alzheimer's can only
be diagnosed after death?
ABBY NOYCE: Definitively, yes.
That is likely to change in the next five or 10 years,
I suspect.
Or at least our non-death requiring diagnosis methods
will get better.
So one of the things that happens with Alzheimer's is
you see tissue loss and distinctive parts of the brain.
You see it in the hippocampus.
You see it in the prefrontal lobes.
You see it in particular regions of the temporal lobes.
You see it along the cingulate gyrus,
which is that part of the frontal lobes where
they nudge up against each other in the middle.
And you can pick out some of that
on an on neuroimaging system like an MRI
as the resolution on MRI gets better.
There's a staining technique--
well, not quite a staining technique, an imaging technique
that works like PET.
Remember in classic PET scans where
you're looking at what parts of the brain are active,
people would drink this radioactive glucose.
And then you'd scan where the radioactivity
was emitted from because it would get picked up
in the blood.
And then it would be sent to the parts of the brain that
were working the hardest.
Somebody has done a modification of that where you have patients
drink a substance that has a radioactive molecule that
will bind to, not to the tau proteins, but to the flax,
to these beta-amyloid fragments.
And so if you have a molecule that will bind specifically
to that and then you can stick a radioactive tracer
onto that molecule and you have this then bind
to these plaques, you can see how much of it
is in somebody's brain.
You can measure the level of it which sticks.
And you can look at the distribution of these plaques.
And there are people working to figure out
what the exact criteria for a diagnosis using this would be.
So like I said, there's better diagnosis tools
kind of in the pipeline right now.
But you know, some people don't want to know.
That's the other half of it is some people
will say no, I'm not going to get tested for this.
I'm not going to get screened for it.
If I'm going to die in seven years,
I don't want to know about it.
AUDIENCE: Why?
ABBY NOYCE: Many people--
this is something that keeps coming up, especially--
Yeah, some people want to know.
And some people don't.
So there's a lot of things like I
don't know if you guys have heard
of Huntington's disease, which is
a neurodegenerative disease that usually first kicks in
around age 45.
It's also heritable.
So one of the things that tends to happen
is people happily have kids in their 20s and 30s.
And then they hit 45 and find out
that they have Huntington's and then realize that they have
probably passed it to their children
go, oh no, I didn't know that, whatever.
And so Huntington's is one of the easy to find,
easy to genetically test for diseases.
It's a mutation on one gene, on one chromosome.
There is one very small chance that we can look at and say
this is the thing that causes Huntington's.
So now you can get tested for it.
You can give a drop of blood through the lab,
and they'll run a screen and they'll test for it.
And some people want to know.
And some people absolutely don't.
They know they have a parent who had it so they
have a 50% chance of having it.
And they do not want to know yes or no for sure.
And you can't require them to get tested or anything.
But this sort of testing starts bringing up
all sorts of issues.
As we get and as we get more and more ideas
about what the genetic bases of different kinds of diseases
are, we're going to see these issues come up more and more.
I don't know.
I was listening to NPR this afternoon in the car.
And they were talking about HIV testing and again
the same thing.
Lots of people don't want to know.
They don't want to get tested.
They don't want to know for an assortment of reasons.
It's an interesting question.
It's a difficult question And some of those cases
where you might know for sure what the answer for you
is but it's very hard to say that the answer for everybody
should be this or that.
So we that these two kinds of cellular molecular changes that
you see in the brains of patients who have Alzheimer's.
So here's again a micrograph of a neurofibrillary tangles
you can see the different strands in here that are all
wrapped around each other.
They make this kind of characteristic flame shape
that you can see in different kinds of staining.
AUDIENCE: It always looks like that?
ABBY NOYCE: It's not always quite that pretty.
But I mean, if you look at this photo micrograph.
So this photo micrograph claims to only
be showing the senile plaques.
But all of these shapes in here--
see these?
I am not a trained cyto-histological person
in identifying Alzheimer's disease characteristics.
But those look very similar to me, in my untrained state,
to photo micrograph I've seen of what
these neurofibrillary tangles look
like that discussed that characteristic flame shape.
So I looked at this and said, you're not
telling me that's what's there.
But I wonder if these are what they are.
So I don't know.
But they do tend to always have this very characteristic shape
where they are narrow on one end and kind of rounder
on the other.
AUDIENCE: And that's just how they form?
ABBY NOYCE: That's just how they form.
remember this is caused by proteins
wrapping around each other in a certain way.
So there's going to be characteristics
of how the charge is on different parts of them are
what's attracted and what's repelled that causes
particular deformations.
So like I said, these are things that you see
in patients with normal aging.
But there's more of them in Alzheimer's patients.
They're distributed differently.
There's kind of an ongoing theoretical argument
about whether Alzheimer's is just normal aging happening
worse in some patients or if it's actually
something that is qualitatively different than normal aging.
And oh hey, terminology moment.
So Alzheimer's is a proteopathy--
which is a word I hadn't heard before actually--
which refers to diseases that happen because of a protein
misfolding.
Issue.
So proteins fold up into a particular shape.
And it's that shape which gives them their function.
Think again about ion channels in the cell,
they've got to have those different subcomponents lined
up in a little cylinder in order to ions in and out.
Of shape is important for proteins.
When proteins go wrong, they can't do their job anymore.
So what causes this?
There's a couple of hypotheses about what the underlying
causes are of Alzheimer's disease.
One of the things we know is that early stage
Alzheimer's tends to involve particularly the damage
to the basal forebrain cholingeric system.
So you guys all remember this is subcortical mostly
kind of towards the frontal lobe subcortical structures where
most of the acetylcholine in your brain
comes from, its cells who have their cell bodies in this area
and then project them through almost all of cortex.
And one thing we know is that these
are one of the first cells to deteriorate and start
to die in Alzheimer's disease.
And one of the oldest hypotheses is that this reduced synthesis
of acetylcholine is the thing that causes Alzheimer's.
There are four medications for Alzheimer's on the market
right now That are approved by the FDA and so on.
Three of them all work on acetylcholine.
They all are acetylcholinesterase
inhibitors.
Acetylcholinesterase is the enzyme
that cleans up acetylcholine out of the synapse
after it's been released by a pre-synpatic cell.
So if you inhibit acetylcholinesterase then
what's going to happen is that every time acetylcholine is
released into the synapse, it's going
to hang around for longer.
It's not to get cleaned up so quickly.
And so at least to some extent, this
can make up for a reduced amount of it being released.
Because it gets to stay around longer, it evens out
It's kind of the same logic as SSRIs
selective serotonin reuptake inhibitors as antidepressants.
If we inhibit the re-uptake of serotonin,
let it sit in the synapse longer,
than it'll make up for a decreased amount of serotonin
being released.
So in this case, we're looking at acetylcholine
from this basal forebrain cholingeric system.
So these acetylcholinesterase inhibitors
work reasonably well.
They definitely have an effect on the symptoms of early stage
Alzheimer's.
They help people who are having memory impairment.
They'll improve that.
They'll improve cognitive function.
It's not huge, but it's definitely an improvement.
That's why they're on the market.
But they don't stop it from getting worse.
It's like this is a Band-Aid sort of solution.
It also really doesn't seem to make any difference
as the dementia progresses as it gets worse.
They stop having really any measurable effect at all.
So this is an early stage treatment.
It treats the symptoms, doesn't stop things from getting worse.
The other medication that's on the market right
now is based on a different idea.
You guys remember we talked about glutamate
when we were talking about long term potentiation in learning
and memory?
So one of the things that happens
that glutamatergic cells have to watch out for
is that if a cell takes up too much glutamate,
it actually will die.
It's called excitotoxicity.
If there's too much glutamate release
into a certain region of the brain,
it will actually kill those cells.
Not sure exactly how this happens.
We're not sure exactly how this happens.
It may have to do with too much calcium coming
in through those NMDA receptors that can let in calcium.
And then the calcium triggers apoptosis which is that
and then the cell basically commit suicide.
The cell says, oops, something is very wrong.
I'm going to kill myself now, shut down, disintegrate.
So apoptosis-- you guys probably remember from bio--
is that programmed cell death.
Cell death where they get some kind of signal
from his surroundings that it is no longer
needed, and it should wrap up its business
as nearly as possible and disintegrate.
So the other Alzheimer's disease medication
is trying to combat this excitotoxicity problem
by working on NMDA receptors.
It's an antagonist for NMDA receptors.
So it sticks to the same spot that glutamate does.
It reacts to the glutamate binding
site on the NMDA receptor.
But instead of opening the receptor channel
the way glutamate does, it just kind of sits there
and blocks it.
So it's not the right shape to trigger it to open.
And it's in the way so the glutamate can't come in
and trigger it to open either.
So again, this medication reduces
that excitotoxocity, but much like these cholinergic
medications, doesn't seem to stop long term
prediction of the disease.
It treats symptoms, and treat symptoms
later then the cholinergic drugs do.
The cholingeric drugs treat early dementia.
The glutamateric drugs seems to reduce symptoms of mid
to late stage dementia.
But again, it doesn't stop the progression.
AUDIENCE: So what effect does that
have on the person if they don't have glutamate
getting into their system?
ABBY NOYCE: So it's not going to block all of the glutamate.
And it's only going to work on the NMDA receptors.
Actually, the side effects for this one are moderately mild.
The side effects are things like slight dizziness and headaches.
Whereas the acetylcholinesterase drugs actually
have some really nasty side effects or they can.
They're kind of rare, because they see the calling is also
the neurotransmitter that's used at the neuromuscular junction.
So if you mess up acetylcholinesterase,
you're also messing up what happens everywhere
your nervous system tells a muscle
to do something, which is your entire body.
And you can get some really weird side effects going on
with those.
A lot of these drugs can have weird side effects
because they aren't as precisely targeted as one might like,
especially for something like Alzheimer's, which affects,
especially in its later stages, pretty much the entire brain.
So this is the cholinergic hypothesis.
This has pretty much gone out of favor,
because you can fix the amount of acetylcholine that's
in the brain, at least for early stages.
But it doesn't actually change how the disease progresses.
So at this point, the reduced amount of acetylcholine
seems to be a symptom of the disease
but not a cause of the disease itself.
So the disease is eating the basal forebrain
cholinergic cells, which then causes
acetylcholine to be reduced.
All right.
So the other is kind of two main causes that are discussed
is that it's either these tau proteins
or these amyloid protein masses that are causing
some amount of cell toxicity.
So the tau hypothesis says that what's happening
is that these tau proteins, for whatever reason,
become hyper-phosphorylated.
They change shape.
The microtubules that they were holding together fall apart.
And when the cell can no longer transport things
down the microtubules to the tips of its axons,
then its ability to communicate with other cells fails.
So first of all, you're seeing these decreases
in cognition that can just be explained by synapses breaking,
down by cells no longer being able to communicate
across synapses.
And over time as the cytoskeleton disintegrates
further, you're going to get apoptosis and programmed cell
death.
So there's just one theory.
There are some researchers who think
that this is what's going on.
There is research being done into it.
But most researchers who are studying
this stuff think that's what's going on
is in this amyloid stuff.
And there's a couple of good theories for this.
So one hypothesis is that these amyloid plaques,
by breaking up the amyloid precursor proteins, that
transmembrane proteins and forming these amyloid plaques
in the extracellular fluid, then this in turn
messes up the calcium balance in the cell.
So the cells have to have a precise amount of calcium.
If they have too little, bad stuff happens.
If they have too much, bad stuff happens.
And it's the presence of these plaques
that causes these cells that have too much calcium inside.
Their calcium homeostasis mechanisms get broken.
Too much calcium, as we discussed a minute ago
with toxicity, can then lead to apoptosis,
to this programmed cell death idea.
These are explanations in particular
not just for the symptoms of Alzheimer's disease,
but for the very specific dramatic cell death
that you see as this disease progresses.
One of the most interesting pieces
of evidence in favor of this amyloid hypothesis
is that that amyloid precursor protein-- remember
that's the big transmembrane protein that gets broken up
to form the amyloid beta that then forms the senile plaques.
So this amyloid precursor protein is on chromosome 21.
And as you guys probably know, trisomy,
if you have three copies of chromosome 21,
you get down syndrome.
Anyone here know anyone with Down syndrome?
There was a kid in my class at school who had down syndrome.
So down syndrome patients have a really characteristic
facial shape.
They tend to have poor vision, poor hearing, low IQs,
all of that.
And the thing about down syndrome
is that down syndrome patients almost always
exhibit symptoms that are very much like those
of Alzheimer's disease.
And they get this early.
They don't get this at 65 or 75 or 85.
Down syndrome patients get this in their late 30s.
They start showing impaired learning, impaired memory,
not just relative to normal IQ people,
but relative to where they were previously.
And it follows pretty much all of the same progression
patterns as Alzheimer's disease does.
And the fact that the chromosome that's involved down syndrome
is the chromosome that has the gene
for this hypothesized cause is a kind
of promising piece of evidence.
And it makes some amount of sense.
These things seem to be related.
Another piece of evidence in favor of the amyloid hypothesis
is that Alzheimer's disease is, at least to some extent,
a heritable disease.
There's a genetic component to it.
And there's a couple of different heritable types
of Alzheimer's that have been traced
to a couple of different genes.
One is a mutation on the gene that produces
this amyloid precursor protein.
There's also a couple of what are called these presenilins,
these enzymes that break up the amyloid precursor
protein to form the beta plaques,
the amyloid-beta plaques.
And mutations for a different form of presenilins
are another heritable form of Alzheimer's, another place
where it's been traced to a particular gene.
So both of these pieces have a genetic basis for the disease
are based around this amyloid beta process.
So also really interesting, so somebody
said, OK, so what if this is what's going on?
What if we could manage to vaccinate people
against Alzheimer's disease?
What if we could manage to immunize them
with something that removes these amyloid plaques?
And I couldn't get the full copy of this,
but I read the abstract.
So these guys-- and this is a brand spanking new paper.
This is in like the July 2008 issue of this journal.
These guys were doing a clinical trial of this idea.
So state 1 clinical trial, you do it
on a small group of patients.
I think they had 80 patients.
And you kind of want to do it on patients who have nothing
to lose, patients who have been unresponsive
to other medications, patients who have a terminal
disease of some sort.
State 1 of clinical trials is the first time
you try this drug on human beings.
You've tried it on your animal models.
It hasn't caused your rats to go into spasms or die or anything.
We think it's safe, we think it's beneficial,
let's move it to humans.
And so what this immunization does
is they have developed a protein that will kind of bond
to the beta-amyloid fragments that
make up these senile plaques and will remove them
from the system.
So it will actually go through and clean up
all of these amyloid plaques.
It will remove plaques.
And so if the plaques themselves are
what's causing Alzheimer's disease, then removing them
should be beneficial.
And so what they found is that the plaques were
between OK and great, is that the immunization
was between OK and great and for patients
at removing these plaque.
So compared to a control group who
did not get the immunization, the patients who did,
the experimental group, it removed somewhere--
for some patients, it was like less than half of the plaques.
For some patients it was almost all of them.
So there was definitely it's having some effect
in decreasing the number of these beta-amyloid plaques
in these patients' brains.
But it did not improve either survival rates, either length
of time from diagnosis to death for either group of patients.
There was no difference.
And it didn't change the rate at which the dementia progressed,
the rate at which it got worse.
So what this is implying is that is that whatever is going on
with the amyloid protein process,
and it still seems to be the best candidate for where
the cause of this is, it's not simply
the presence of the plaques in patients' brains
that's causing this decline.
The plaques also seem to be a secondary symptom rather than
an immediate cause of Alzheimer's.
All right, questions?