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[From A Report on Alzheimer's Disease and Current Research by Dr. Jack Diamond, scientific director of the Alzheimer Society of Canada]
Other Leads for Earlier Diagnosis and New Treatments
Vaccines
There are promising developments here. Vaccines
became a real possibility when animal models of
Alzheimer's disease were created (that is, genetic
engineering was used to get the genes for familial
Alzheimer's disease into mice). The brains of these mice
develop amyloid plaques and the mice are memoryimpaired.
Researchers then designed a modified A-beta which,
when it was injected into the mice, induced their
immune systems to make antibodies against it.
Because the modified A-beta was so like the normal
A-beta, the antibodies they generated also worked
against the A-beta already in the brain, and the result
was a significant reduction of the plaques and an
improvement in the cognitive abilities of the mice.
Human trials were rapidly undertaken, only to be
dramatically stopped in 2002 when some of the
participants developed alarming brain inflammation
(this didn't happen with the mice).
So where do we stand? Well, new modified A-beta
vaccines are being vigorously sought – and found –
that are predicted not to cause brain inflammation.
Also, new mouse models are now being produced with
neurofibrillary tangles in the brain cells, and anti-tangle antibodies are being made and tested. In one new
approach the vaccine is given as a nasal spray, which
is claimed to stimulate the brain's immune cells (the
microglia), which then will mop up the excess A-beta
molecules. In another approach, instead of giving
substances which will stimulate the production of
antibodies (active immunization), already manufactured
antibodies are provided directly (made either in animals
or cultures of living cells). This approach, called
passive immunization, bypasses the immune system of
the body, hopefully thereby reducing the chances of
triggering adverse inflammation of the brain. Finally
a new experimental vaccine has been created which
targets neither A-beta nor the “tau” protein of the
tangles, but instead it targets one of the key enzymes
involved in splitting the toxic A-beta from its big
parent protein. While much remains to be found out,
a number of these exciting animal studies have already
been extended to human clinical trials, and the early
news gives definite hope that within five to seven years,
there could well be a vaccination therapy that could
revolutionize the treatment of Alzheimer's disease.
MCI
Some important developments relate to MCI, a
condition that is being increasingly found in early
middle-aged and even young adults. MCI is clearly an
important risk factor for the disease. Brain imaging is
showing that abnormal changes almost certainly exist
in the brain even before MCI is diagnosed, and indeed
even in some totally non-MCI people's brains that later
developed symptoms of Alzheimer's disease. Some
researchers believe that plaques may begin to appear
as early as 5 to 10 years prior to any signs of dementia.
Imaging approaches, added to psychological testing,
should make it possible both to pick out the most at-risk
MCI individuals, and to assist enormously in the early
diagnosis of Alzheimer's disease. This is important:
earlier diagnosis means earlier treatment, and the
sooner a therapy is started the better. Many (but not all)
clinicians are now recommending that cholinesterase
inhibitors be given to people diagnosed with MCI
without waiting for signs of Alzheimer's disease
to appear.
Statins
These cholesterol-reducing agents are being investigated
because the incidence of Alzheimer's disease appeared
to be less for people using these drugs to lower their
cholesterol levels. At first it was assumed that the benefit
of these statins came from their ability to reduce the
incidence of cardiovascular disease (diseases affecting
the heart or blood vessels), which is a risk factor for
Alzheimer's disease. However, we now know that statins
also reduce the production of A-beta from APP, so
here is another promising future treatment strategy.
Moreover, since cholesterol is a key component of
the membranes that enclose nerve cells, abnormal
cholesterol levels could seriously alter cell membranes,
and the responses of nerve cells to substances such
as growth factors, hormones and of course drugs.
Keeping cholesterol from rising above normal levels is
clearly very important.
Alzheimer's disease and diabetes
As discussed in the section on Risk Factors, research on
people with Alzheimer's disease and on animal models
of the disease is showing that, even when diabetes in the
conventional sense is absent, anti-diabetic drugs called "glitazones" can help maintain brain function and,
seen in the animal studies and assumed to occur also in
people, reduce the development of brain plaques. This
approach is supported by the observation that insulin
administered through the nasal passage, which can get
preferentially to the brain without going through all
the rest of the body, improved memory and cognition
in some people – a promise of future therapeutic
measures.
Anti-inflammatory agents such as aspirin and other NSAIDs (nonsteroidal anti-inflammatory drugs)
Although not yet proven, there is intriguing evidence
that people routinely taking anti-inflammatory agents
for rheumatic and other conditions are at a decreased
risk of getting Alzheimer's disease, and this lead is
being followed up. Cannabinoids (cannabis-derived
substances) have also been claimed to have antiinflammatory
and other benefits in Alzheimer's disease,
but at present the potential dangers associated with their
numerous actions in the nervous system make their use
problematical.
Other drug therapies
Flurizan™ is an example of a new class of drugs
currently in clinical trials. Flurizan and other "secretase
inhibitors" work by blocking the process that splits off
A-beta from its big parent molecule, APP. This helps
to stop the dangerous accumulation of A-beta in the
brain. Other drugs, including cyclohexanehexol, a new
agent discovered by Toronto reseachers, interact with
the A-beta molecules as they form, and prevent them
from sticking together in small aggregates - aggregates
that poison nerve cells and eventually deposit as
solid "plaques", but by the time they form most of
the damage is already done. Alzhemed™ is another
such drug, but its initial promise was not supported
in expanded clinical trials, and it has now been
discontinued. Other treatments aim at encouraging the
mopping up of the A-beta before it reaches threatening
levels. Ubiquitin is a naturally-occurring chemical in
the brain that helps in this mopping up action, but its
levels are reduced in Alzheimer brains. When mice with
Alzheimer's disease were given drugs that increased
their ubiquitin levels, their brain function improved
even when the amyloid plaques persisted. Presumably
this was because the drug prevented the very small
toxic aggregates of amyloid from developing. Iron,
zinc and copper, which are virtually impossible to avoid
in normal diets, are needed for the A-beta molecules
to clump to form the toxic oligomers, and they have
been suggested as risk factors for Alzheimer's disease
in certain individuals. This possibility is being tested
in trials of a drug called Clioquinol that helps remove
the suspect metals from the body. Definitive results are
not yet in from these studies. Finally ginkgo biloba, a
herbal supplement purported to improve memory, is in
clinical trials to see if it affects the onset or severity of
Alzheimer's disease.
It has long been hoped that biological markers for
Alzheimer's disease would appear in various tissues
that could be more easily accessed and studied than
the brain itself. New findings are offering hope that
early diagnosis may become possible through such
biological markers. Recent reports described two such
in the skin of people with Alzheimer's disease, firstly
an abnormal inflammatory chemical response that is
easy to detect, and secondly, the presence of abnormal
levels of a number of proteins. Other studies on people
with Alzheimer's disease are revealing alteration in their
CSF levels of A-beta and tau, the two proteins most
implicated in Alzheimer's disease. The search goes
on for biological markers of Alzheimer's disease, and
scientists are hopeful.
Stem cells and their promise
Researchers are very excited at the prospect of replacing
lost nerve cells in Alzheimer brains by using special
cells known as stem cells. These are immature cells that
have not yet developed to the stage when they show
a recognizable mature identity, that is, one that would
label them as nerve cells, heart cells, liver cells, and so
on. Stem cells occur naturally in most of the body's
tissues, such as bone marrow, skin, and also the brain,
and apparently are used as a source of replacement cells
to be recruited whenever tissue degeneration occurs due
to disease or trauma (part of the body's natural repair
strategy). There is evidence that the repair function
offered by resident stem cells converting into nerve
cells can happen spontaneously after traumatic brain
injury, and even in neurodegenerative conditions like
Alzheimer's disease. The aim of Alzheimer researchers
is to encourage this process, but even more so to obtain
a reliable and abundant "outside" source of stem cells
and then to get them into the regions of the brain
where nerve cell degeneration has occurred. What are
the chances of achieving this aim?
Stem cells are multipotent, or pluripotent, meaning
that under appropriate conditions any stem cell can
transform into any particular adult cell types. This
transformation is brought about in the body, and also
in the experiments done by researchers, by exposing
the stem cells to 'trophic' substances, also called
growth factors. These factors are natural nourishing
molecules made especially in the embryo to guide the
development of stem cells along the road to becoming
specific mature cells, but trophic factors are also made
continuously throughout life to help maintain the health
of virtually all the cells in the adult, including nerve cells.
One of the most important of these trophic molecules,
the first such to be discovered actually, is called Nerve
Growth Factor, or NGF for short. NGF is needed
especially to keep the brain cells involved in memory
and thinking alive and well, and therefore, as explained
following, is of special interest as a potential treatment
in Alzheimer's disease. The stem cell replacement
approach is being very actively studied in experimental
animals, and in some countries preliminary tests
have begun in people with Alzheimer's disease, with
ambiguous results.
Where will the stem cells come from?
A persisting problem has been how to obtain the
substantial numbers of stem cells needed for their study,
and will certainly be needed if they're going to replace
cells lost in diseases like Alzheimer's disease. In theory
this can be solved, once a source of stem cells has been
established, by transferring the cells to a special chamber
containing an appropriate nutrient broth in which they
are "cultured", i.e. allowed to grow and divide, which
they will do readily and apparently indefinitely. The
most popular source of stem cells to date has been
embryos or fetuses, in which stem cells are abundant,
and also from the amniotic fluid that surrounds the
fetus. There are, of course, ethical considerations in
obtaining stem cells from human fetuses, and Canada,
in common with many other countries, has important
limitations on stem cell research in this regard. However,
two recent research reports have cast an entirely new
light on the situation. Using a 'retrovirus' as an infecting
agent, certain molecules known as 'transcription' factors
were introduced into fully developed human skin cells.
Transcription factors regulate (or "activate") genes.
Using the virus, the researchers effectively shuttled
up to four transcription factors into mature skin cells.
These factors were already known to be highly active
in stem cells, but not in adult cells. The effect of these
transcription factors was to activate genes that converted
the adult skin cells back into an earlier and more
primitive state, into cells in fact that closely resembled
normal embryo-derived stem cells. In the jargon, the
skin cells were 'reprogrammed'; their original adult
character was lost, and instead they looked and behaved
like normal immature stem cells. The excitement
generated by these two reports was not just because of
the discovery of how to transform normal adult cells
into stem cells, but because of the implication that stem
cells could now be obtained without the involvement of
human fetuses. So the question becomes – how near are
we to using stem cells reliably and safely as replacement
nerve cells in people with Alzheimer's disease?
Pluses and minuses of stem cells as potential replacement cells
Some big pluses – When any foreign tissue or cells
are transplanted into a person, their immune system
immediately starts to work to get rid of what it views
as potentially harmful invaders. This is called ‘rejection',
and to prevent it the host recipient has to be given
immune-suppressants. This is hazardous, because
now the body is being deprived of its most important
defense against dangerous threats such as infection and
the development of tumors. A wonderful advantage
of using skin as a source of stem cells is the possibility
of using the skin of the person him or herself, thereby
allowing for a replacement cell strategy without the
complication of rejection. This reasoning is a powerful
plus in favor of creating a skin-derived stem cell
industry. Moreover, because of the 'immortality' of
stem cells already referred to, once they are obtained in a
laboratory setting they constitute a persisting source of
continuously dividing stem cells that needs no renewal.
Are there drawbacks? Indeed yes - there always have been
problems associated with the idea of a stem cell therapy whatever
the source of the cells.
i) the genetic make-up of the stem cells created using
retroviral infection of adult skin cells described in
the new reports mentioned above was not identical
to that of conventional embryonic stem cells. It's
not yet known how abnormal the consequences
of these genetic differences might be. One major
concern is that the use of a retrovirus might
introduce the potential for initiating tumors in
the host body, or of causing undesirable genetic
mutations in neighboring cells. Moreover,
reprogrammed adult skin cells might still contain
DNA abnormalities caused by earlier exposure
to sunlight or environmental toxins, hazards that
could carry over to the newly created stem cell
population.
ii) There is other evidence that laboratory cultured
stem cells are not guaranteed to convert into totally
normal adult cells. In some earlier Canadian studies
stem cells (actually obtained from adult skin) were
transformed into what looked like perfectly normal
nerve cells, but it turned out that some critically
important mechanisms required for the cells to
produce nerve impulses (messages) were missing--
an important defect by any standards!
iii) To promote useful functions any nerve cells
implanted into the brain have to become correctly
integrated into the existing neuronal circuitry. The
implanted material has to be positioned at the
right anatomical sites, the new nerve cells have to
be recognized by other nerve cells as appropriate
targets with which to make new connections, and
they themselves have to grow out nerve fibres that
will make connections with the correct receiving
nerve cells.
What are the chances of these circuitry needs being successfully
accomplished?
Daunting though these problems may seem, there
is an unexpected kind of evidence which supports
the possibility of implanted nerve cells becoming
appropriately integrated into the host nervous system.
It seems that "cues" exist, even in adult nervous
systems, which help guide newly-growing nerve
fibres to correct destinations. Apparently some of the
mechanisms that operate during early development, to
ensure that the correct connectivity is achieved, survive
into adulthood. That such mechanisms were once there
is clear. Were they absent, and supposing that trial and
error were ultimately responsible for ending up with
the correct connectivity in the brain, this would take
literally hundreds of years to achieve rather than the
months of fetal brain development. So, provided that
neuroscientists are able to implant stem cells, or stem
cells already transformed into adult nerve cells, into the
required brain locations, it could be that enough new
connectivity would spontaneously develop to maintain
or restore functions threatened by disease or trauma.
In the case of Alzheimer's disease, the brain regions
involved in memory and cognitive functions would be
the prime ones to receive such implantations.
How long before we have a viable stem cell replacement
therapy? The best guess of this writer is decades at
the very least. This is not to deny the potential of
such therapy, which offers a direct solution to the loss
of nerve cells in the brain. But while we await this
desirable result, it's encouraging to know about the other
promising treatments that are on the horizon.
Promoting brain repair
The special importance of
stem cell studies and others now to be mentioned is that
they address the problem of brain repair. If the brain
functions that are lost in Alzheimer's disease are to be
restored, the brain damage must eventually be reversed.
Even when a truly successful treatment for Alzheimer's
disease appears, i.e. one that actually stops the disease in
its tracks so that there's no further brain degeneration,
there will still be the need to deal with the damage that's
already happened. We have to cure the person as well
as the disease! Of great importance here are the growth
factors such as NGF described earlier. Growth factors
also stimulate nerve cells to sprout new branches and
make new connections to make up for those lost as
neighbouring nerve cells die. This compensatory nerve
sprouting helps recovery after stroke and brain trauma,
for example. Unfortunately it doesn't occur so readily
in aging, and it is also reduced by some of the known
risk factors for Alzheimer's disease. Scientists are now implanting genetically engineered cells that make NGF
into the brains of animal models of Alzheimer's disease,
and in one study NGF-producing cells were implanted
directly into the brains of people with Alzheimer's
disease. Initial results show promise both for keeping
nerve cells from dying and in improving cognition and
memory.
It is certain that the three approaches, delivery of
growth factors, delivery of stem cells, and mobilizing
stem cells already resident in the brain, will one day pay off as a way of reversing the damage caused by
Alzheimer's disease. However, all of this will take quite a
few years. Another more immediate and quite different
way of promoting brain repair is described in the
following section.
[The contents of this page are provided for information purposes only and do not represent advice, an endorsement or a recommendation, with respect to any product, service or enterprise, and/or the claims and properties thereof, by the Alzheimer Society of Canada. The information contained in this report was current at the time of printing, April 2008.]
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