Preventing Dementia MOOC

What is Dementia?
Video Transcript

Professor James Vickers

Dementia is a term that we use to refer to a change in functioning from
previous levels. The domains that are affected by dementia include your higher
cognitive abilities, personality and behaviour. There are many dozens of
diseases that will actually cause dementia, and most of these are associated
with advanced ageing, although some, particularly with a high genetic
predisposition, can occur at much younger ages.

The four major neurodegenerative diseases that cause dementia are

Alzheimer’s Disease, Lewy Body Disease, Frontotemporal Dementia and
Vascular Dementia. And sometimes these occur singularly and they can also
occur in combination. And it’s these four that we’ll focus on in the presentation
today.

The major cause of dementia is Alzheimer’s Disease, and this probably accounts
for around 50% to 60% of cases. We know that Alzheimer’s Disease is
characterised by specific pathological changes that occur inside the brain, and
these were originally described by Alois Alzheimer at the beginning of the 20th
century. The three changes include those that happen at the macroscopic level,
which involves shrinkage or atrophy of the brain, and this can affect particular
structures of the cerebral cortex, including the frontal lobe, temporal lobe and
parietal lobe. The other two pathological changes occur at the microscopic
level, and these are neurofibrillary tangles and amyloid plaques. Amyloid
plaques are spherical structures that occur between nerve cells and are
comprised of a protein known as A-beta. Now A-beta is a normal protein that
you would find in all of our brains, but in Alzheimer’s Disease, it undergoes an
abnormal transformation. It forms small fibrils that accumulate together to
form plaques, and where plaques form in the brain, they cause damage to
nerve cells, particularly the processes of nerve cells, the axons, the dendrites, as
well as synaptic connections between those nerve cells. The other major
microscopic change that occurs inside the brains of people with Alzheimer’s
Disease is the neurofibrillary tangle.

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Now, within all nerve cells there’s a fine meshwork of filamentous proteins that
we refer to as the cytoskeleton. When a nerve cell is affected by Alzheimer’s
Disease, this cytoskeleton collapses and is replaced by the neurofibrillary tangle.
The main protein that comprises this tangle is an altered form of a normal brain
protein we refer to as tau. Now, tangles probably take many years to actually
develop within nerve cells, and they seem to follow the initial development of
plaques within the brain. They are also very insoluble structures, which means
they don’t dissolve very easily. So when a nerve cell dies, usually the tangle is
left behind, and we refer to this as a tombstone or ghost tangle. There are new
imaging technologies that are being developed for Alzheimer’s Disease that
might help us visualise these amyloid plaques and neurofibrillary tangles inside
the brains of people while they’re alive. If we combine the data from these new
studies with that which has been derived from pathological studies, we now
appreciate that there’s a particular sequence of pathological change that
occurs inside the brain with Alzheimer’s Disease.

It seems likely then that plaques may occur many years, sometimes as many as
ten to fifteen years, before you develop overt symptomatology. The plaques
appear to precede the neurofibrillary tangles and the neurofibrillary tangles
themselves are more closely linked with the loss of synaptic connections
between nerve cells, which lead to the pattern of symptoms. In this regard,
Alzheimer’s Disease is a degenerative and progressive disorder in that the
disease develops from one stage to the next - from a clinical silent period,
where plaques develop inside the brain, through to the initial stages of the
disease, which can be insidious and often difficult to detect, then through to
the progressive deterioration in higher cognitive functions. One of the early
cognitive functions that seems to be affected by Alzheimer’s Disease is short-
term memory and the ability to form new memories.

In Alzheimer’s Disease, we know that particular brain regions are vulnerable to

degeneration, and even within those brain regions, certain nerve cells are
particularly susceptible. One of the structures of the brain that’s affected early
in the disease is the medial temporal lobe, and as this degenerates, you may
see some symptoms, such as an inability to form new memories and difficulties
generally in short-term memory. But then the disease progresses to other brain
regions, to other lobes of the cerebral cortex, and as this occurs you will see
difficulties in other higher cognitive areas, as well as behaviour and personality,
and this might include planning ability, logical thinking, orientation in space
and time, as well as language.

The speed of progression, as well as the age of onset, of Alzheimer’s Disease

does vary between individuals. We don’t really understand why this is the case,
but it’s likely mainly due to genetic predisposition, but other lifestyle factors
may well play a role.

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In Alzheimer’s Disease, there are likely to be a range of genetic risk factors that
contribute to your relative risk of developing this condition. The best known
one, and the one that has the most impact on your risk, is the apolipoprotein E
gene. Now, this comes in three variations – Epsilon II, Epsilon III and Epsilon IV.
You inherit one version of this gene from each of your parents. Essentially, the
more of the Epsilon IV version of this gene you have, the higher risk you have of
developing dementia as you get older. In less than 5% of cases, there’s a much
stronger genetic predisposition and we often refer to this as familial forms of
Alzheimer’s Disease. We know of three genes that carry a range of mutations
that can cause familial Alzheimer’s Disease. One of these is the amyloid
precursor protein gene, and we know that this is then linked potentially to the
production of amyloid beta that forms the plaques in Alzheimer’s Disease.

Another cause of dementia is Lewy Body Disease. Now, this is known by a

variety of terms, including diffuse Lewy Body Disease, Dementia of the Lewy
Body Type and Alzheimer’s Disease with Lewy Bodies. The cardinal pathological
feature of Lewy Body Disease is the presence of an abnormal proteinaceous
inclusion inside nerve cells called the Lewy Body. Now, the Lewy Body is a
spherical structure made up of proteins, fine filaments and lipids. It also occurs
as the main pathological feature of Parkinson’s Disease, and we think that
Parkinson’s Disease and Lewy Body Disease are related to each other. Some of
the clinical features of Lewy Body Disease may well include motor problems
that you see in Parkinson’s Disease, such as tremor. Similarly, if you have
Parkinson’s Disease for a long period of time, you may then develop cognitive
issues that are very similar to what we see in Lewy Body Disease. Inside the
brains of people with Lewy Body Disease, you’ll often also see amyloid plaques,
and this probably speaks to some kind of interrelationship between Lewy Body
Disease and also Alzheimer’s Disease.

Another cause of dementia is Frontotemporal Dementia, and this is really a

spectrum of different diseases. Broadly, they’re characterised by dramatic
shrinkage, or atrophy, of brain regions, such as the frontal lobe, and the frontal
sections of the temporal lobe. The symptomatology of the disease broadly
follows the damage to these cortical areas – for example, with frontal lobe
damage, comes changes in personality and behaviour, as well as higher
cognitive skills, such as planning and judgement. With damage to the temporal
lobe, there’s often problems with language and speech production.

Of all of the conditions that cause dementia, frontotemporal dementia

probably has the strongest genetic predisposition. So around about 30% to 40%
of cases of frontotemporal dementia are likely linked to particular genetic
mutations. And because of this genetic predisposition, these cases tend to have
a relatively early onset.

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Vascular dementia is sometimes known as multi-infarct dementia, and this
involves an interruption to the normal blood flow into the brain. In most cases
of vascular dementia, this involves damage and disruption to the small blood
vessels that penetrate through the brain, particularly in the white matter tracks
underlying the cerebral cortex. In other cases of vascular dementia, there might
be a series of small strokes occurring in different regions of the brain. Vascular
pathology is actually quite common with advanced ageing and this vascular
disease can coexist with other forms of dementia, such as Alzheimer’s Disease.

These different forms of dementia are the focus of intense study globally. We
are trying to understand the sequence of pathological changes that lead to
dementia. In many cases, this is probably largely attributed to advanced ageing,
as well as your genetic predisposition, but we’re also interested in how more
modifiable risk factors may play out in terms of the disease pathology.
Ultimately, we’re interested in therapeutic agents that might modify disease
progression, so might have an effect on the specific pathological hallmarks, or it
might be that we can look at interventions that might improve on your relative
resilience to these dementing disorders.

From the Preventing Dementia MOOC h t t p s : / / m o o c . u t a s . e d u . a u

©2023, Wicking Dementia Research and Education Centre, University of Tasmania
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