Dementia is an insidious disease that
gradually and subtly  steals a lifetime
of memories our personalities our ability
to live independently and eventually our
lives
it describes a set of symptoms such as
forgetfulness confusion and
disorientation which occur when the
brain cells are damaged by disease or a
series of strokes. Around 47 million
people are affected worldwide, a figure
that's expected to double every 20 years
with much of the increase occurring in
developing it costs 818 billion dollars
worldwide 1.1 percent of world gdp
Put simply dementia is the biggest
medical and social change facing
humankind.
By studying the basic building blocks of
life,  mini brains grown in a lab and
worldwide populations researchers at
Cambridge have one aim to stop dementia.
Dementia is actually a global name that
that we use to describe and  group together
a series of different illnesses that
that all affect the brain in the same
general way. The most common form of
dementia is Alzheimer's disease
about two-thirds of dementia is caused
by  Alzheimer's disease, then there are other
forms well. Vascular dementia is probably the second most common cause and then the
rare ones as well such as Frontal
temporal dementia, dementia with lewy
bodies. Dementia is not the same as
normal aging and is considered a
distinct condition however aging itself
is a major major risk factor for
dementia the changing risk is not simply
changing chronological age there's
something that is occurring when one ages
that dramatically influences ones
likelihood of getting Dementia.
But it is not only the old that are affected
around one percent of cases of
Alzheimer's disease are caused by
genetic variant found in family lines
Andrew king is one of these people his
wife Sarah started noticing some unusual
behaviour, car accidents, confusion and
underperforming in his role as a
geneticist at the Sanger Institute where he worked.
After a long series of tests he was
eventually diagnosed with early-onset
dementia, he was just 43 years old.
Dementia didn't even cross the horizon
because we thought it was kind of .....If anyone had asked
we thought that was an old person's
illness. We got the diagnosis and then
within a couple years he couldn't walk
properly he was  doubly incontinent and having
problems eating and went to the care home and within...about 8 tears ago, so he must have
been 45 he was having to be fed by tube and then he's been pretty much
the same since then.
Although much is known about the
mechanisms behind the development of
dementia there is no known cure.
It is very
difficult thing another example in the
history of Medicine where we've got the
level of understanding about the disease
that we now have Alzheimers and that
hasn't led to therapeutic benefits.
The traditional approach to dementia is
nothing can be done but today you are
telling us you are turning around this
approach to say something can be done.
At the 2013 G8 dementia summit
health leaders from across the world
pledged a research ambition for a
disease-modifying therapy for dementia
by 2025. Alzheimer's Research UK has
formed a new drug discovery alliance
that will make a major contribution to
delivering this ambition a UK-wide
network of Institute's dedicated to
early-stage drug discovery.
So our Cambridge drug discovery institute is part of
an alliance of three of these DDIs with
Cambridge, Oxford and UCL and really what
we're doing is building an embedding
drug discovery expertise and experience
to work alongside the great researchers
here who are finding out more about the
mechanisms of disease. The purpose of the
Institute's is firstly that they work
together, they co-oporate to some extent and so
it's to bridge the gap which currently
exists between academic scientists and
the initiation of drug discovery
projects. The initial stage in drug
discovery is to understand what actually
happens in the brain to cause the
disease
In 1906 Dr. Alois Alzheimer first
discovered what we now know to be the
hallmark Alzheimer's proteins. He was
assigned to the case of Auguste Deter a 51
year old woman who is admitted to the
Frankfurt Mental Institution with
typical symptoms of what we now call
dementia. Upon her death Alzheimer
discovered strange plaques and tangles
in her brain. Plaques are abnormal
clusters of the protein Beta amyloid
that build up between nerve cells in the
brain. Tangles are caused when fibers of
tau proteins twist together a process
first identified by Dr. Michel Goeder
at the MRC Laboratory of Molecular
Biology. In the nineteen eighties we
showed that the TAU protein is an integral
component of these filaments that form
inside nerve cells from where they spread
to distant brain regions and it is this
spread of brain too distant brain
regions that causes the symptoms of
Alzheimer's disease so understanding the
mechanisms underlying the spread might
allow one in the end prevent the spread
from occurring and therefore the
symptoms of Alzheimer's from
appearing.
Even in a healthy brain
plaques and tangles develop normally
with age but they are found in much
greater abundance in people with
Alzheimer's. They start accumulating in
areas of the brain associated with
memory and learning and then spread to
other areas
In the Department of Clinical
Neurosciences Professor Peter St George
Hislop, looks at how small changes in
the instructions carried by some genes
can lead to the creation of these
abnormal proteins, with abnormal functions.
Over the last several years we we've
described and discovered about 20 different
genes that are associated with risk for
Alzheimer's disease and we're doing the
same thing for the other causes dementia
like frontal temporal dementia and so the
next step is now to take those jeans and
ask how it is that variance in those
genes
increase the risk for developing the
disease. We know for some of the genes
that they alter the processing of a
protein called amyloid precursor protein
or APP which generates this neurotoxic
amyloid beta peptide some of these other
genes they seem to have a different way
of acting and so we're going to try and
work out what that mechanism is, how they
work and the longer term is once we
understand the function of each of those
genes, to then be able to try and find a way
in which you can block that abnormal
function and ultimately at the end of
the day what we might be able to do is
to say somebody has a variant in this
gene there are at slightly increased risk
of developing disease so that person
should be given that treatment and
another person who has perhaps and
another genetic variant increase their
risk might require a different treatment
that is specific for their particular
type of the disease.
Professor Chris Dobson and his
colleagues Dr. Tuomas Knowles and
Professor Michele Vendriscolo
at the Centre for Mis-folding diseases
have been studying amyloid and similar
proteins to understand how they fold
into functional structures and what
causes some proteins to miss fold into
the wrong shape and generate disease.
When proteins are made they're made as long
chains of amino acids from the
information contained in in our DNA had
to function they have to fold up into
specific structures. We have these
natural protective mechanisms that did
keep our proteins in good shape and
functional and if they mis-fold and
aggregator clump together then they're
cleared but at some point these can
become overwhelmed and then you start to
accumulate these species in the brain and
dementia and even worse they're they're
sort of catalytic and the disease
progresses very rapidly. Once we started
to understand the.. if you like the
mechanism by which proteins mis-folded
then we began to think about how that
can be prevented and what we've been
doing then is actually to try to find
small molecules in particular that then
and inhibit specific aspects of the mis
folding reaction and two particular
aspects of this that we're very excited
about the moment. One is the idea that
you can take a molecule but like a
statin is sometimes called Neurostatin and
we called it a Neurostatin that reduces
the risk that you would actually get
Alzheimer's disease and the other is is
that if one clearly has symptoms of the
disease can we develop small molecules
that will reduce the rate at which it
progresses or even how we could actually
enable the brain to recover from these
processes and and we have a number of
these molecules that we've found inhibit
the processes in the test tube
we've been looking at
how they can do that and simple model
organisms such as fruit flies or the
nematode worm and and we've been very
excited about the results because we
seem to be able to suppress these
processes very effectively and so the
next step is to take those further and
to see how we can develop them
potentially as drugs to use in the
clinic. The cells in our body have their own
natural way to remove dysfunctional
proteins before they become toxic and
start to destroy brain cells
this process is called autophagy and is
a key stage in treatment development is
being researched by Professor David
Rubenzstein's team. Autophagy is a
process that cells use to get rid of
parts of the cytoplasm that's the bit of
the cell that's outside the nucleus and
in doing so the cells form a double
membrane structure which engulfs
proportional the cytoplasm to form a
vehicle which we call modify the autophagasome
and then it delivers the order autophagosome
to the lysosome which is the cellular
incinerator for degradation and this
allows the removal of parts of the
cytoplasm and in this case of the
neurodegenerative diseases these
aggregate toxic proteins. We've
worked very hard to understand the basic
biology of the process to identify
therapeutic targets but also to try to
identify drugs that you might be able to
use in people that can enhance this
process reduce the levels of these toxic
proteins and ameliorate the signs and
symptoms of the disease.
It is thought that the clusters and abnormal proteins
that cause plaques block signals passing
between nerve cells in the brain and
promote a process that leads to
disintegration of these cells
the twisted tangles of TAU proteins are
thought to block the movement of
nutrients around these brain cells which
then die.
Professor Giovanna Malucci and her team
are looking at slowing or preventing the
process of cell death and where the
damaged cells can be repaired. Well,  there
are two strands, two main strands to the
laboratory. The first has identified a
really fundamental process that happens
probably in almost all of the diseases
that cause dementia or neuro-degenerative process they call protein
mis-folding disorders and how that mis-
folding of these proteins causes the
brain cells to die.
We've also discovered how to manipulate
that process both using genetic tweaks
but also using chemicals drug like
compounds and we've cured degenerative
diseases in mice. But this this compound
is toxic to the pancreas, protects the
brain but is toxic to the pancreas. We've
moved on from that we found another
compound that protects both brain and
pancreas but it's so insoluble so that
the question is about  drug discovery
and improving the kind of compounds that
will do the same job but with minimal
side effects.
Once potential compounds or drugs are identified the next step is to
test them to see which our best to take
forward into clinical trials
It is hoped that research into each of
these mechanisms and processes that lead
to dementia will ultimately reveal drug
candidates that can be tested on humans
in clinical trials. But this takes time
and money.
Within the Gurdon institute Dr. Rick Livesey's research has identified a
remarkable modeling technique using stem
cells to replay Alzheimer's disease in
the laboratory.  What we do here is we
make human neurons in the lab but we do
that starting from individuals patient's
skin cells and so based on technologies
developed around the nobel prize from
Professor John Gurdon the founder here we
can turn skin cells back into stem cells
Now stem cells in principle can make every
cell type in your body in our case we use
them to make the part of the brain that
affected by Alzheimer's disease
The overwhelming majority of Alzheimer's
disease affects people in their mid to
late sixties but there's a rare
inherited form of Alzheimer's disease
which affects about one percent of
people with Alzheimer's so this is the
familial or the genetic form of the
disease which runs in families and
it's due to changes in just one gene
within your DNA. What that means is people
with the familial Alzheimer's disease mutations  develop early onset
Alzheimer's disease typically in their
late thirties or early forties so what
we do is we make stem cells from
individuals who carry this familial
Alzheimer's disease mutations. What
that allows us to do then is to compare
disease to what actually happens within
the ninety-nine percent of people who have
the sporadic or later onset form of
the disease. The advantage of using stem
cell systems to study Alzheimer's
disease means that we're actually
studying real human neurons within the
lab so the neurons are actually affected
by the disease we also study it over a
much shorter time frame so typically
months in our case it rather than years.
Stem cell systems are also useful in
accelerating the drug discovery process
and Alzheimer's disease
there are a number of different
candidate drug treatment of development
but the real challenge to choose which
ones to then progress and use in
clinical trials. What stem cell systems
allowed to do tests which ones look like
they work within the different Alzheimer's
disease models
and that actually allows us to
prioritize in one which would really
effective ones which don't and it's as
important to succeed as it is to fail a
drug discovery early on in the process
so we don't waste time putting drugs in
the clinical trial which actually then
aren't effective in patients.
One of the big challenges in discovering a drug to
treat dementia is that we have to try to
understand when the best approach or
time to take the drug would be and that
really requires us to understand
what's going on within the brain as the
disease develops and so it's very
important that we also carry out
research in things such as imaging to
help us identify patients who are at
high risk of getting the disease.
We know that it's not really possible to diagnose to mention the very early
stages just from clinical signs and
symptoms and here we're using particular
brain imaging but also other methods
looking at changes in the blood to try
and see which biomarkers are the best
for diagnosing dementia at the early
stages. So one very exciting development
is that we're having two brand new
scanners installed here in Cambridge one
is what's called a high field strength
magnetic resonance imaging or MRI
machine and that allows us to look at
brain structure and function in much more
detailed and were able to at the moment
and the second is a machine that
combines MRI and another form of brain
imaging PET and that would allow us in a
single scan to get information both on
the structure of the brain and also on
the chemical composition and protein
composition of the brain so they're very
exciting developments for us.
But drug discovery may not be the only answer to reduce the prevalence of disease
despite predictions on the rate of
increase of dementia new studies show
that improvement in our lifestyle are
working. The number of new cases and
overall numbers of dementia seem to be
stabilizing in some Western European
countries. In the early nineteen nineties
Professor Carol Brayne's and her team conducted a
multi-site study across the UK to
determine the prevalence of dementia in
the over 65
A recent repeated this study has revealed
some dramatic results
What we found was that ...the amount of dementia.. if you fix the age age group
the amount of dementia that there is at
any given age has gone down by more than
twenty percent and that means that
something is happening within our
populations and within our brains that
protects that may be protecting us and
to make predictions we need to
understand how whole populations have
lived their life courses. Professor Brayne
has used whole population studies to try
to understand how early life, education
nutrition, exposure to alcohol and drugs
and exercise affect the prevalence of
developing dementia. There seems to be one
common link. We know that education,
educational level protects us from the
expression of dementia during life
however we don't know whether
the education effective is because
people of education do more exercise or
it could be a whole range of different
things but we do know that having a
having more education in early life
having a more
intellectually stimulating
job in midlife
and social engagement in later life all
of those things are associated with a
lower risk of   dementia.
The importance of
the brain healthy lifestyle is clear and long-term studies are invaluable but the
burden of dementia continues to have an
explosive impact on our global
population. For the millions of people
around the world whose lives have been
directly affected by this devastating
condition it's vitally important that
the search for new ways to treat and
prevent dementia continues.
The vision that I would have is that we design our treatments and our approaches to support people with dementia and mental
decline towards the end of life
appropriately so that we're not trying
to as it were cure, cure it with a
single pill
but having a very well a very smart approach to
it
understanding that these things will
need different approaches but integrated.
It would be important to Andrew to know that
they're more treatments available for
people like Andrew so that people can
have a good quality life as long as
possible and their families can have 
them
remember their family and their friends can have that person around
for long as possible.
There's no reason why given the level of
understanding about the biology of
Alzheimer's disease, to my mind there is no reason
why we should not be able to develop effective treatments in the future.
We're very very excited about being able
to quite soon get these into patients
and see if we can, we can, we can impact
the progression if you can stop
progression we can stop it in the same
way that we've shown works in mouse models
that's incredibly exciting times.
What I think we should aim to do is buy  individuals who are at risk of getting these
diseases as many years of good life as
possible and so if we can delay the onset
of the disease we
will be accomplishing that. Indeed if we can delay the onset of the disease beyond the normal life span
we've cured the disease. I believe Alzheimer's
disease is eminently treatable and by
bringing together the expertise that 
exists in Cambridge from different
disciplines is already leading to a new
understanding of the origins of this
disease and that new understanding will
generate new types of therapies, new
drugs that will transform our view of this disease
in the future.
