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Well, thank you very much, all of you,
for coming out on a first sunny day in a few in Colorado,
and learning about where we are in our understanding
of the problem of Alzheimer's disease,
and where we hope to be in a very few years
with both your help as potential
donors, supporters, caregivers,
and, unfortunately, sometimes patients
that will help us solve this problem.
Now, to give you an idea of what this problem entails,
if you look around the room, basically,
if everyone in this room lives to be 85,
half of us will have Alzheimer's disease.
And because of the advances of medical care and support,
many of us will live to be 85.
Cancer is not cured, of course,
but it's managed in many cases.
Heart disease is beginning to go down
because people are living more healthy lifestyles.
And then they live to be
what we would call their golden years
and are faced with this problem of Alzheimer's disease.
Now, it turns out, as indicated in this first slide,
that people with Down syndrome
are giving us tremendous insights
into Alzheimer's disease because, in fact,
people with Down syndrome
and people with Alzheimer's disease
are two sides of the same coin.
Okay, so many of you know
somebody who has Alzheimer's disease.
You may have read about Alzheimer's disease in the paper.
So, I'll just go through very briefly
what Alzheimer's disease is
so as to correct any misperceptions
and give you some foundation
upon which we can build this story.
So, the majority of Alzheimer's disease
is what we call sporadic,
which is a scientist term of saying
we don't know what causes it.
We know something about what causes it, but not completely.
These occur in people over the age of 65,
and, as I indicated, about 50% of people over 85.
Now, there is also a purely genetic form
of Alzheimer's disease, which is extremely rare.
And we'll talk a little bit about that
because it's given us great insight to the disease.
This occurs in people in their 50s,
in their 40s, in their 30s,
and sometimes even in their late 20s,
depending upon the mutation that that family carries.
And then, as I indicated in the title,
Down syndrome individuals
are a very special group of people who,
because they have three copies of chromosome number 21,
instead of two copies like everybody else has,
they have a propensity for developing Alzheimer's disease,
which essentially guarantees that their brains,
by the age of 40, look like an Alzheimer's disease brain.
And more than half of them develop dementia
by the time they're 50 or 60.
So in addition to all the other challenges they have,
they all develop Alzheimer's disease pathology
and most dementia.
So Alzheimer's disease is, obviously,
a neurodegenerative disease of the brain.
That means that nerve cells die
and the connections between nerve cells die.
And over the course of time to death,
the brain shrinks tremendously, as indicated here.
Now, brain shrinkage alone is not
the indication of Alzheimer's disease.
These, what we call neuritic plaques,
and these neurofibrillary tangles
are the hallmarks of Alzheimer's disease,
which Alzheimer himself found in 1907.
Without these two lesions that occur by the millions
in the parts of the brain involved in cognition and memory,
you won't have Alzheimer's disease.
And that's essentially
what we knew about Alzheimer's disease until 1985,
when George Glenner and Kenny Wong
isolated the protein in the amyloid deposits
and sequenced it and found this peptide.
Now, you can memorize it if you like,
and there'll be a test at the end of the day,
but I haven't memorized it,
and so that would be a waste of your time.
But this peptide with 21 in his first study,
and then we now know 40 or 42 amino acids,
is the key to developing Alzheimer's disease.
It's a natural product of the brain,
but it occurs in greater amounts
in people with Alzheimer's disease.
Now, that alone was not enough
to tell us what causes Alzheimer's disease.
So, what happened is that in those families
that have inherited Alzheimer's disease,
some of them actually have a mutation
in the gene that causes
the production of that amyloid peptide.
And here's a family like that.
You can see over many generations these black squares
are the people that get Alzheimer's disease.
And basically, if a person has Alzheimer's disease,
50% of their children get Alzheimer's disease too
at about the same time.
And the gene for Alzheimer's disease is on chromosome 21.
Here's the chromosome,
here's the amyloid precursor protein gene.
And that explains why people with Down syndrome
get Alzheimer's disease
because they have three copies of chromosome 21
instead of two copies.
They make more of the APP protein.
They make more of the A-beta peptide.
So there are two genetic ways
that you can get Alzheimer's disease
that I've discussed so far.
One is you can have Down syndrome.
You get an extra copy of the gene.
Or, as in this family, you have a mutation in that gene.
Now, what does this help us
to understand Alzheimer's disease?
Well, one of the problems
with Alzheimer's disease for that first 70 years
was that there was no animal model
for Alzheimer's disease.
Now, it's true that monkeys
get a kind of Alzheimer's disease if they get older,
but there are ethical and financial reasons
you can't use large numbers of monkeys.
And polar bears get Alzheimer's disease a little bit,
but I know my dean doesn't want me to have
a lot of polar bears in the lab.
So many of us had to deal with a lack of an animal model,
and that was solved by taking the gene that is mutant
in the families that have inherited Alzheimer's disease
and putting it into a mouse.
Now, mice normally don't get Alzheimer's disease,
but if they have the human gene
that gives humans Alzheimer's disease,
then they get Alzheimer's disease.
And we know that because,
no, they don't know who the president is,
and they don't know what they had for breakfast,
but they also can't figure out how to get around a maze.
Now, this is a water maze where we put the mouse here,
and they can swim around.
They're pretty good swimmers.
They don't mind swimming.
And if they get to this little glass platform
right out underneath the water, which they can't see,
but they can climb out of, they can get out of the water.
And this is a tremendous benefit because
normal mice, once they get on that platform,
they can always find it again.
They look around the room.
They see where the clock is, where the door is,
where the investigator is standing.
They have a spatial understanding of where they are,
and they go to that platform right away.
If they have Alzheimer's disease
because of this mutant human gene,
then they can't find that platform.
All of this has then allowed us to understand
the structure of the brain in an Alzheimer's patient,
why they develop Alzheimer's disease,
and why that gene is so important.
So, here's the amyloid precursor protein
that I discussed that is created by a gene on chromosome 21.
The amyloid peptide that Glenner and Wong found
happens to be cleaved out of this precursor
and make this little A-beta peptide.
And normally it gets cleaved here,
so that's pretty harmless.
But if it gets cleaved here, then the peptide is generated,
and it tends to make fibers
by sticking to itself and making long fibers
that aggregate into sort of Brillo pads
in the brain by the millions,
which kill the nerve cells that are nearby.
And this A-beta peptide has this curious feature
that it tends to aggregate
and make these filaments all by itself.
And furthermore, in the brains
of people with Alzheimer's disease, there's another protein,
which we call ApoE4, or ApoE3, or 2.
And it turns out that if you inherit
an ApoE4 allele from one of your parents,
you have a threefold increased risk
of developing Alzheimer's disease.
So, that's a risk factor.
It's not a genetic guarantee, but it's a risk factor.
And if you happen to inherit ApoE4
from both of your parents, you have two copies,
we have two copies of every gene,
and both of them are ApoE4,
then you have a tenfold increased risk
of developing Alzheimer's disease.
And the reason is because ApoE4 helps
the A-beta peptide make itself into fibers.
So, everyone in this room can take a look at this picture,
this diagram, and you say,
"Well, all we have to do is keep this from happening."
And the scientists agree with you.
And they have developed inhibitors
of the gamma secretase enzyme
and the beta secretase enzyme.
They've created inhibitors, as we have,
of the ApoE4 interaction with A-beta.
And there are ways to keep A-beta from killing cells.
So, all of these steps in this pathogenic pathway
are subject to investigation
to develop new treatments for Alzheimer's disease.
And many of them work pretty well in the mice,
and they're now being tested in humans.
So far, unfortunately,
none of them have worked great in humans.
So, we don't have a new drug.
The drugs that are available basically are band-aids
to help the neurons that are left work a little bit better.
But we have great hope,
especially with respect to this interaction here,
that these drugs will come soon.
Now, the reason it's so difficult
to treat Alzheimer's disease with these drugs
is because it turns out
that Alzheimer's disease in the brain starts
about 20, maybe 30 years before the symptoms are apparent.
So, if you're walking around
and you're 70 years old and you're fine,
you have a 50-50 chance that Alzheimer's disease
has already started.
And we know that for several reasons.
First of all, the dementia comes fairly late in the disease.
But before that,
you have what we call mild cognitive impairment.
And with special tests, we can detect that.
And then before that, you begin to have
problems with brain shrinkage
and with the development of those tangles,
and the amyloid deposits can start much, much earlier.
So, for instance, a person with Down syndrome
may have the full-blown Alzheimer's disease brain
by the time they're 30 or 40,
but we can detect it in the teens
and even younger than that in those people.
Okay, so what about these people with Down syndrome?
Why do I say that they're two sides of the same coin?
I mentioned that they all get Alzheimer's disease pathology,
and most of them develop dementia.
But we had an interesting idea, or I did,
a couple of years ago,
many decades ago, actually.
And that was that maybe the fact that
people with Down syndrome
have three copies of chromosome 21 might give us a hint
about how typical Alzheimer's disease develops.
So here's Professor Lejeune,
and he was the one with an associate of his
who found that there were three copies of chromosome 21
in people with Down syndrome,
and so came up with an idea that maybe
the fact that you have three copies of chromosome 21
in people with Down syndrome might give us a hint
that over the course of the life of a person
that develops Alzheimer's disease,
they actually develop cells
with three copies of chromosome 21.
They're not born that way like people with Down syndrome,
but they have a hidden disorder
that has occurred during their life
that generates these cells
with three copies of chromosome 21.
And so, I wrote up a theoretical paper,
I submitted it to a journal, and I got rejected.
That happens a lot,
but this rejection was pretty bad.
I wouldn't recommend publishing this manuscript
anywhere at any time.
Very few people get that kind of rejection,
but we didn't pay attention to it.
We sent it to another journal,
American Journal of Human Genetics.
They published it, and it turned out to be true.
So how do we prove that?
We make predictions.
Scientists make predictions based on hypotheses.
And if the predictions are right,
then the hypothesis is right.
And if the predictions are wrong,
then the hypothesis is wrong.
So, what's the first prediction?
Okay, that Alzheimer's disease individuals
should show trisomy 21 mosaicism.
We also might predict that if you see mosaicism,
there's an increased risk of developing Alzheimer's disease,
and also that maybe those genes and proteins
that are carrying mutations that cause Alzheimer's disease
should have something to do with chromosomes.
So we tested each of these,
and the first one is done by just counting chromosomes,
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, in the microscope.
Or we can make a little probe
that lights up in the microscope fluorescent,
and this particular cell has two copies of chromosome 21.
Pretty easy to count that way.
So, what did we find out?
We found out first that the skin cells
of people with either sporadic Alzheimer's disease,
one form of mutant Alzheimer's disease,
all forms of mutant familial Alzheimer's disease,
they all contain about 5% of cells
with three copies of chromosome 21 instead of two copies.
This has been repeated, and many cells in the body,
including brain cells, including nerve cells in the brain,
have three copies of chromosome 21.
Here's some very nice work from Iourov
and you can see that about 10% of the cells in the brain
have three copies of chromosome 21
instead of two copies if you have Alzheimer's disease.
So, they're mosaic Down syndrome,
and this was completely hidden.
It developed silently, surreptitiously
over the course of their life
until suddenly they came to clinical attention
and eventually died, and we can count their chromosomes.
Now, is this important?
Maybe it's just a side effect of Alzheimer's disease.
It turns out to be absolutely critical
because from this work by Thomas Arendt in Leipzig
turns out that at the beginning of Alzheimer's disease
or normal individuals,
they don't have too many of these funny cells
that have the wrong number of chromosomes
cause you see it's not just chromosome 21,
it's the other chromosomes as well.
As they get Alzheimer's disease,
they get almost 30% of the nerve cells in the brain
have the wrong number of chromosomes.
And then, as they get more developed Alzheimer's disease,
late, late, late stages of Alzheimer's disease
where they're almost comatose,
the number of aneuploid neurons goes down,
back to almost normal.
And he could calculate that from this point to that point,
there was a lot of cell loss.
And the cell loss was specifically in those aneuploid cells,
the cells with the wrong number of chromosomes.
And you could calculate that 90% of the cell death
that led to the atrophy,
the shrinkage of the brain
in people with Alzheimer's disease
was the loss of these aneuploid cells.
So the aneuploid cells are abnormal.
And because they die,
you begin to develop cognitive problems.
So, that became the indication
that the first prediction is absolutely correct.
Second prediction,
well, if you confine people with trisomy 21 mosaicism,
it should predispose them to developing Alzheimer's disease.
And Nicole Schupf made a very interesting observation
a number of years ago
in which she found that mothers
who had a child with Down syndrome
when they were less than 35
had a five-fold increased risk
of developing Alzheimer's disease.
Now, if they had the child when they were older,
then there was no increased risk.
And the parent, the father,
also didn't have an increased risk.
It was only if they were young.
And then Migliore came along and applied our theory,
and he found out that the blood cells
in the women who had a child with Down syndrome
when they were less than 35
have almost a four-fold increased,
four or five-fold increased risk
of chromosome missegregation for chromosome 21.
They were developing these Down syndrome cells
even when they were young
and just had a child Down syndrome.
So that makes now sense
because they were probably mosaic Down syndrome.
They didn't know it.
That increases the risk of Alzheimer's disease,
and it increases the risk of developing
a child with Down syndrome.
These data are new.
They're not new, but they are not yet repeated
by many, many other investigators.
So it's unclear whether it's absolutely 100% true,
but it makes completely sense,
and these two are very good investigators.
So we think that that satisfies the second prediction.
Third prediction is that the genes and proteins
should be involved in cell cycle,
in chromosome segregation.
Remember that family that had an APP mutation?
We took it out and put it into a mouse.
What about that mutation?
Does it cause problems with chromosomes?
And the answer is, yes, it does.
If you look at that mouse,
that mouse has cells in its brain
that have the wrong number of chromosomes.
This is for chromosome 16.
We stain it with a stain that tells us
that it's a nerve cell.
And look at how many extra cells that are trisomy 21,
sorry, trisomy 16, 'cause this is a mouse,
in the brain of that mouse.
Furthermore, if you take the A-beta peptide
and you add it to cells and culture, 48 hours later,
many of them have the wrong number of chromosomes.
And that's shown here.
This is two daughter cells.
Used to be one cell.
It was treated with the A-beta peptide.
You can see that this daughter cell,
instead of having two and two,
has three copies of chromosome 21,
sorry, 12, and one copy of chromosome 21.
This has three copies of chromosome 21
and one copy of chromosome 12.
So, they just switch places,
and that happens in the culture.
We know exactly what the mechanism is.
And we're now trying to develop drugs
that will prevent it.
That if we take early enough,
it might help prevent
the formation of those aneuploid cells.
Now, I don't know whether you have ever heard
of frontotemporal lobar degeneration,
but it's a kind of dementia
that is similar to Alzheimer's disease,
but it's caused by other kinds of mutations.
And it turns out that some of them have those tangles,
some of them have another kind of deposit in the brain,
and every single type of frontotemporal dementia
has trisomy 21 cells in the brain.
No one ever thought of looking.
We looked, and every single type of
frontotemporal dementia,
sporadic, progranulin mutations,
tau mutations, C9orf72 mutations,
which I don't have to explain in great detail,
but they're mutations that cause
frontotemporal lobar degeneration.
Chromosome 21, chromosome 12,
they all have the wrong number of chromosomes
in the nerve cells in the brain,
and that's shown here that it's not only the glial cells
that are the support cells in the brain,
but the nerve cells themselves.
And so this says that this whole idea
that there is this silent catastrophe
that is building up in the brains of people
that eventually will get Alzheimer's disease,
or, in this case, frontotemporal dementia,
is due to cells with the wrong number of chromosomes,
including trisomy 21 Down syndrome cells.
What about other degenerative diseases?
Niemann-Pick disease is a terrible childhood disease,
and it turns out that the nerve cells in those children,
when they die, have trisomy 21, as do the glial cells,
as do the skin cells.
So this is a completely different disorder.
It has to do with cholesterol metabolism.
We went on to study that,
and we found out that cholesterol, all by itself,
when added to cells, can cause them to
segregate their chromosomes incorrectly
and generate trisomy 21 cells.
And that's interesting because high cholesterol
is one of the risk factors for Alzheimer's disease.
Okay, simple conclusion,
there is a silent problem that is developing in all of us.
All of us have some of these trisomy 21 Down syndrome cells.
But when they accumulate in large numbers,
and especially in the brain,
then they can generate these diseases
that we detect in the clinic,
but the problem has started probably decades before.
And we're now trying to develop drugs that would prevent it
and ways to diagnose it early
to see this problem arising.
And I thank you very much for your time.
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