- In this video, I'm going to talk about
the biological basis of Alzheimer's disease.
Alzheimer's.
And there's disagreement whether to use the apostrophe S,
whether to call it Alzheimer's or just Alzheimer disease.
I'm a little bit more used to this, so I'll use this.
Alzheimer's disease is the most common disorder
in the category of disorders called the dementias.
Dementia.
Or with newer terminology,
called the neurocognitive disorders.
What these disorders involve is
a loss of cognitive functions.
Cognition.
Cognition is kind of the thinking functions of the brain,
and Alzheimer's disease, in particular,
usually starts with a decreased ability
to form new memories.
So the main early complaint is memory troubles
with Alzheimer's disease.
And then those memory troubles progressively worsen,
and later other cognitive functions
usually progressively deteriorate as well.
Other people start to notice that the patient
gets confused or disoriented.
There may be episodes of getting lost
and having progressive difficulty with things like
work, driving, shopping, cooking, or managing finances.
As the disease progresses,
in addition to cognitive abnormalities,
emotional and behavioral abnormalities also often occur,
but other nervous system functions,
like basic motor and sensory functions, are usually spared
through most of the course of the disease.
At later stages, when Alzheimer's disease
becomes most severe, patients lose the ability to perform
what are called basic activities of daily living.
I'll just write ADL for short.
But these basic activities of daily living
include things like toileting, bathing, dressing, or eating,
and these patients will eventually require
full-time nursing care to attend all of their bodily needs,
because they won't be able to
take care of those things themselves.
This is a famous image
when talking about Alzheimer's disease,
because this was the first patient
that was described with Alzheimer's disease.
This person was studied by Dr. Alzheimer,
and that's why the disease is known by that person's name.
As of 2014, when I'm making this video,
our understanding of the cause of the disease
is very limited.
To show you some of the things that can be seen
abnormal with the brain with Alzheimer's disease,
I have a few illustrations of the brain.
Here we're looking at the brain from the left side.
Here we're looking up at it from the bottom,
from underneath, and then here are a few illustrations
showing the brain as if it's been cut just like this,
and we're looking at the inside of the brain tissue
and the layer of tissue on the outside.
And when we compare brains from people
without Alzheimer's disease
and people with Alzheimer's disease,
the really obvious finding, when looking with the naked eye,
is that the brain tissue has decreased in size.
So you can see that this brain is kind of
shriveled up and wasted away,
compared to this brain without Alzheimer's disease.
The medical term for a decrease
in size like this is atrophy.
Let me just write that word down.
Atrophy.
And all this word atrophy means is that
the bulk of a kind of tissue has decreased.
It's decreased in size.
And with Alzheimer's disease, it's the cerebrum,
this topmost part that's colored
in these different colors here,
that often dramatically decreases in size.
The severity of the atrophy often correlates
with the severity of the dementia.
So the patients with really severe cognitive deficits
often also have dramatic shrinking of the volume
of the tissue of the cerebrum,
like they're showing in this illustration here.
This atrophy usually starts in part of the cortex,
which is the layer on the outside of the cerebrum,
and it particularly tends to start
in what are called the temporal lobes.
These are the temporal lobes,
if we're looking up at the brain from underneath.
Let me just write that.
Temporal lobes.
And here in this illustration, they've shown this as well.
They're showing a normal brain
with a normal amount of brain tissue,
and next to it they're showing a typical brain
for a person with severe Alzheimer's disease,
where the overall brain tissue has decreased,
and in particular, these areas of the temporal lobe,
these kind of inside parts of the temporal lobe,
and these parts we know are particularly important
for forming new memories.
So these parts tend to atrophy first,
which goes along with the early clinical abnormalities
of Alzheimer's disease of having trouble
forming new memories.
Later, atrophy develops in many cortical areas
of the temporal lobe, the parietal lobe,
and the frontal lobes.
So, widespread cortical areas of the cerebrum
develop atrophy as the disease progresses,
and these other areas that atrophy we know are important
for many of the other cognitive functions that are
typically affected by the disease.
Under the microscope, like in this actual photograph here,
taken with a microscope of some of this
cerebral cortical tissue of a person
who passed away with Alzheimer's disease,
there are three main abnormalities that can be seen
with typical microscope studies.
The first is that we can see loss of neurons.
So neurons are clearly lost from the brain tissue
in these areas of cerebral cortex
that are actually decreasing in size
to the naked eye as well.
So people go through microscope slides
of these areas of cerebral cortex
and count up the neurons.
They'll see a decreased number of neurons.
These sorts of cells right here are neurons
within the rest of the brain tissue surrounding them.
The second abnormality are called plaques.
Plaques.
And these are some of the types of plaques that can be seen.
These are also called amyloid plaques,
because they're made up of a protein
called beta-amyloid primarily.
These amyloid plaques occur in the spaces between cells.
So they're outside of the neurons of the brain,
in the space between them,
and they're these abnormal clumps
of this beta-amyloid protein.
The third typical finding are called tangles.
Tangles or neurofibrillary tangles,
and I don't think we can see that at this magnification,
but if we looked through with a higher magnification
at some of these kind of sicker looking neurons,
like maybe these guys,
within them we would probably see these
neurofibrillary tangles, which are abnormal clumps
of a different protein called tau,
and these neurofibrillary tangles
are located inside neurons.
So the amyloid plaques are in the space between cells,
and the neurofibrillary tangles made up of
these abnormal clumps of tau protein are inside of neurons.
Both of these abnormalities develop from proteins
that are normally present in the brain,
beta-amyloid and tau,
but for reasons that are not yet fully clear,
these proteins are changed in some way that's abnormal
that causes them to clump together
and form these amyloid plaques and neurofibrillary tangles.
Here an artist has drawn something going abnormal
with processing of this beta-amyloid protein
that leads to them clumping together
to form these amyloid plaques.
And here an artist is trying to show
these neurofibrillary tangles inside of diseased neurons
and how this tau protein can abnormally clump together
inside the neuron to form these neurofibrillary tangles.
So we can see these things on microscope slides
of brain tissue affected by Alzheimer's disease,
but it's actually not totally clear yet
if the problem is that these things form
and that kills the neurons in the brain,
causing the loss of neurons,
or if these things are just a byproduct
of some other process
that's causing the loss of the neurons,
so that even if we fix these problems
of the amyloid plaques and the neurofibrillary tangles,
it's not yet totally clear if that would prevent
the neurons from being lost in the brain.
A particular group of neurons at the base of the cerebrum,
around here, called the basalis nucleus, basalis,
or it has a longer name of the nucleus basalis of Meynert,
the neurons in this nucleus, this group of neurons
is often lost early in the course of Alzheimer's disease.
These neurons appear to be important for cognitive function.
These neurons send long axons to many areas
of cerebral cortex throughout the cerebrum,
and what they do is release the neurotransmitter
called acetylcholine, acetylcholine,
and loss of this diffuse projection of acetylcholine
from the basalis nucleus to the cerebral cortex
appears to contribute to
the cognitive dysfunction of the disease,
because certain medications that affect
this neurotransmitter system often improve
some of the symptoms of Alzheimer's disease.
One of the very interesting findings
in people studying Alzheimer's disease
is that long before cerebral atrophy
or the microscopic abnormalities develop,
and years or even decades before cognitive loss occurs,
there appears to be abnormalities of energy use
and abnormalities of many of the molecules
related to energy pathways inside brain cells.
There's evidence that the metabolism
of the primary fuel source of brain cells,
which is called glucose,
and the function of mitochondria,
which are organelles that are a primary site
for energy metabolism, both appear to be abnormal
long before the other abnormalities appear.
Also, there have been some findings
regarding the affects of cellular energy use,
which are called oxidative stress,
which appears to be increased,
and oxidative stress is known to be
a potential source of damage to brain cells.
But so far, the cause of these changes is unclear.
Another very early finding is that synapses,
the place where neurons contact
and communicate with each other,
appear to not function normally
long before the other abnormalities are seen,
and the cause of this is also unclear.
Many things have been associated with
the risk of developing Alzheimer's disease,
which may play some role in causing the disease,
at least in some people.
These include multiple genetic mutations,
many of which involve processing of the protein
beta-amyloid, the primary component of amyloid plaques.
There's also another gene, called ApoE4, ApoE4,
that's strongly associated with
the risk of developing Alzheimer's disease,
but it's involved in metabolism of fats in the body,
so it's unclear how it's related as well.
And then there are very separate things,
like medical conditions that cause
dysfunction of blood vessels, such as high blood pressure,
appear to increase the risk of the disorder as well.
And then on the other hand,
certain things appear to decrease the risk
of developing the disease,
or at least seem to delay it's onset in some people,
and these include having greater amounts of education
and working at cognitively challenging jobs
that involve lots of difficult thinking,
but how all these different things could interact
to affect the cause or course of Alzheimer's disease
is still very unclear.