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Alzheimer's - and the
Pharmaceutical industry
Understanding Alzheimer's
The past 25 years can rightly be described as ‘the age
of the brain’. In particular, developments in scanner
technology have enabled us to see the functioning brain at
work, while advances in molecular biology have enabled us
to explain many of the brain’s miraculous achievements
at a biochemical level. We have also gained an insight, albeit
incomplete, into the malfunctions that lead to mental illnesses
such as schizophrenia, epilepsy, and depression, as well as
degenerative disorders such as multiple sclerosis, Huntington’s
chorea, Parkinson’s and Alzheimer’s. Most exciting
of all, these developments have provided new ideas for the
design and discovery of new medicines.
Research into the illness has been especially rapid, so much
so that we can now describe with some accuracy the changes
that occur in the brain of people with Alzheimer’s on
the large, microscopic and molecular levels. Here we will
briefly survey this information and then use it in later sections
to consider how current Alzheimer’s medicines are thought
to work, and how it is guiding scientists towards new strategies
that might halt mental decline or even prevent it happening
in the first place.
The normal and Alzheimer’s brain
compared
The normal healthy adult human brain weighs about 1400g (3
lbs). The outside is covered with a complex pattern of folds
called convolutions, while inside, there is an outer
layer of grey matter forming the cerebral cortex, an
inner layer of white matter, and an interconnecting system
of cavities called ventricles, which are full of cerebrospinal
fluid. When floating in its cerebrospinal fluid, the brain
only weighs about 14 per cent of its weight in air, and is
thus provided with buoyancy and a shock-resistant cushion.
By comparison, a brain from a person who has died from Alzheimer’s
will have shrunk, the folds on the outside deepened and widened,
the proportions of white and grey matter changed, and the
internal cavities enlarged. By the time of death, an Alzheimer’s
brain is likely to have lost between 30 and 50 per cent of
its weight.
The brain is fed by several large arteries which carry about
1700ml (three pints) of blood to the brain every minute. This
blood supply is its only source of nutrients and oxygen: the
brain uses 20 per cent of the oxygen requirements of the whole
body. If this blood supply is interrupted by, say, a large
blood clot, brain damage will quickly occur, resulting in
a stroke. If there are many small blood clots (mini-strokes)
over a period of years, the cumulative damage may lead to
vascular dementia, which is responsible for about 20 per cent
of dementia cases in the elderly.
The development of advanced scanner technology has also made
it possible to observe differences in the behaviour of the
normal compared with the Alzheimer’s brain in living
people. There is clear evidence from positron emission tomography
(PET) scans that the brain of someone with Alzheimer’s
uses glucose and generates energy at a far lower level than
that of a healthy person, thus reflecting the decline in mental
function. However, in some people, these changes occur very
slowly, while in others, they are much more rapid.
Other studies using magnetic resonance imaging (MRI) scanners
in Alzheimer’s show that brain tissue is not lost evenly
throughout. Certain regions, notably the hippocampus
and the cerebral cortex, appear to be much more affected
than others. Again, this seems to fit the pattern of the illness,
because the hippocampus is intimately involved with memory
processing and the frontal cortex with logical and rational
thought, so-called cognitive processes.
Cell loss in the Alzheimer’s brain
These large-scale changes just described are now known to
be caused by the loss of nerve cells (neurons). At
birth, the brain contains over 100 billion of these –
the same as the number of stars in the Milky Way. Each one
may have between 1,000 and 10,000 connections with neighbouring
neurones through filaments called dendrites and major junctions
called synapses. Hence the total interconnections present
may number up to 100 trillion – a figure beyond human
comprehension. Even the most powerful computers in the world
today are crude machines compared to the exquisite complexity
of the human brain. In addition to neurons, the human brain
also contains billions of other specialised cells. Two of
these are called astrocytes and microglia. The
function of the former is to absorb and distribute nutrients
from the blood stream, while the latter help remove debris
and repair damage.
After birth, neurons are lost at a rate estimated to be up
to 1 million a day, and they are rarely, if ever, replaced.
This sounds a lot, but even after a lifetime, it only represents
about 10 per cent of the total. This probably contributes
to ‘normal’ ageing such as forgetfulness in the
elderly, but by and large, the remaining neurons compensate
and there is no significant loss of mental function. Neurons
often run in trunks interconnecting different parts of the
brain, rather like the bundles of wires in a car wiring loop.
Some of these trunks are particularly vulnerable in Alzheimer’s,
and so many neurons are lost from them that the remainder
cannot compensate, with consequent devastating effects.
Neurons transmit messages between themselves and to organs
all over the body. Such messages travelling within neurons
are electrical in nature and are responsible for the ‘brain
waves’ that can be recorded with electrodes placed on
the scalp (an electroencephalogram or EEG). However,
the passage of a nerve signal from one nerve to the next across
the synaptic cleft is brought about by small molecules
called neurotransmitters – rather like the baton
passed between runners in a relay race – which bind to
receptors on the next neuron.
It is now clear that there are many different types of neuron
and each may use several different kinds of neurotransmitter.
A type of neuron central to Alzheimer’s depends heavily
for its function on one called acetylcholine (ACh).
In Alzheimer’s, such neurons are lost more than any other.
As a result, the amount of an enzyme that makes acetylcholine
(choline acetyltransferase – ChAT) falls in the
brain compared to the levels in normal elderly people, followed
by a decline in acetylcholine itself. The story is a little
more complicated though, for as long ago as 1914, Sir Henry
Dale found that there were two types of receptor for acetylcholine,
one called muscarinic and the other nicotinic
– named because they were stimulated by muscarine or
nicotine respectively, which mimic the effects of acetylcholine.
Microscopic studies show that the regions of greatest neuron
loss are within nerve trunks connecting control centres such
as the hippocampus with the cerebral cortex – just those
regions where greatest brain shrinkage is seen. However, it
also reveals that many of the remaining cells look unhealthy.
Between the neurons are abnormal blobs called senile
or amyloid plaques while within them are found neurofibrillary
tangles. The amyloid plaques are dense structures and
nearby neurons are often swollen and distorted. Scavenging
cells called microglia that react to local inflammation are
also present – a sign that they may be attempting to
eradicate and repair sites of brain damage.
Some amyloid plaques are also found in the normal ageing
brain, but they are far more abundant in the hippocampus and
cerebral cortex of people with Alzheimer’s, and they
develop before neurofibrillary tangles can be found. Scientists
have believed for many years that a key to understanding Alzheimer’s
lies in the mode of formation and chemistry of amyloid plaques
and neurofibrillary tangles. Such information will also be
vital for the development of new medicines, so it is not surprising
that these structures have been the subject of intensive study.
The Alzheimer’s brain at the
molecular level
In the 1980s it was shown that neurofibrillary tangles were
composed of an abnormal protein called tau which helps
form and maintain minute tubes called microtubules.
These give shape and support to neurons, and provide a transport
system for nutrients and other substances inside cells –
rather like the Underground system in London allows the transport
of people and goods within the city.
In Alzheimer’s, the structure of tau is faulty
and the microtubules are damaged. The faulty tau collects
in neurons, where it clumps together to form twisted deposits
called paired helical filaments, visible in the electron microscope.
These form the tangles which clog up the cells and further
disrupt their function. The amount of tau present is often
related to the severity of the dementia, but because it is
also found in some other conditions, its role in Alzheimer’s
is unclear.
The composition of amyloid plaques has also been studied
in great detail. By 1984, the main component had been found
and named beta-amyloid peptide (BAP). BAP was found to arise
from a molecule called beta-amyloid precursor protein (ßAPP)
which was chopped into smaller pieces by specialised enzymes
called secretases in the membranes of neurons. Most of these
small pieces are cleared from the brain, but one, called BAP42,
is not. Instead, it forms deposits between the neurons to
form amyloid plaques, which then damage and kill nearby nerve
cells. Clearly, if this process could be prevented, the illness
may be averted. Separate studies showed that the gene for
ßAPP is located on chromosome 21 – the same one
that is also implicated in Down’s syndrome. Significantly,
Down’s syndrome individuals usually display Alzheimer’s-like
symptoms by the age of 40. Also, in families with inherited
forms of Alzheimer’s, mutations are found in the gene
coding for ßAPP which increased the formation of BAP42.
In 1993, scientists found a link between another gene called
apolipoprotein E (APOE) and Alzheimer’s. APOE
has an important normal function, helping repair and regenerate
ageing cells, but was found to exist in three different forms
called  2,
3
and 4.
Studies in people with Alzheimer’s showed that 40 per
cent of them had the 4
form. It seems that people with 4
are less good at removing BAP and so develop more amyloid
plaques. Most strikingly though, people who possess 4
as well as a mutation in ßAPP develop Alzheimer’s
much earlier in life.
In 1995, two other genes on chromosomes 14 and 1 were identified,
called presenilin 1 and presenilin 2 respectively.
Mutations in them increase the amount of BAP42 formed and
are also found in cases of early-onset Alzheimer’s.
In summary, this evidence suggests that Alzheimer’s
is a partly genetic, progressive condition characterised by:
- the development of neurofibrillary tangles inside neurons
and
- the formation of neurotoxic beta-amyloid peptide and plaques
which together
- cause damage to, and the death of, neurons especially
those using acetylcholine as their chemical messenger, eventually
leading to
- shrinkage of the brain due to this cell loss, especially
in the areas concerned with memory, rational thought and
speech.
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