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Trends in Biomedical
Science
Prospective Treatments for
Alzheimer’s
For each of the following think
about:
1. What the treatment does
2. Why it may be helpful
There is no treatment that can cure
Alzheimer’s or even halt its progress,
but there are some medications that
can temporarily alleviate the cognitive
deficits associated with it. In just about
half of all patients who respond to these
medications, the reduction in symptoms
begins 3 to 6 months after the start of
treatment, and lasts an average of 6 to
12 months.
But the efficacy of these
medications is hard to
assess, because of
variations in their dosage, in
how long they are
administered, in the route by
which they are administered,
and so on.
The class of drugs most
often used to treat
Alzheimer’s are the
anticholinesterases, or
cholinesterase inhibitors.
Another medication, memantine,
works by inhibiting the brain’s
glutamate receptors. Like the
anticholinesterases, it is only
moderately effective and has no
great impact on the course of
the disease.
These medications appear to
be more effective when
taken early, in the mild to
moderate stages of the
disease.
Anticholinesterases work by
preventing a class of enzymes
known as cholinesterases from
breaking down acetylcholine.
Acetylcholine is a neurotransmitter
that is especially important for
memory and attention and is
produced by neurons that are easily
affected by Alzheimer’s.
Anticholinesterase
medications thus
increase the
concentration of this
neurotransmitter in the
brain.
The first anticholinesterase
medication to be approved as a
treatment for AD was tacrine, in
1994.
But tacrine had bad side effects,
especially on the liver and the
digestive tract.
Between 1997 and 2001, three
new second-generation
cholinesterase inhibitors came
to market that were just as
effective as tacrine but better
tolerated, and tacrine was taken
off the shelves.
But they still have mild to
moderate digestive side effects
(nausea, vomiting, loss of
appetite, diarrhea) in 10 to 20%
of patients. Also, all three can
become less effective over time,
because the neurons of people
with Alzheimer’s produce less
and less acetylcholine.
The fourth medication now
commonly prescribed for
Alzheimer’s is memantine.
Memantine is classified as an
antiglutamate. In 2003 it was
the first medication approved
for use in people with moderate
to severe Alzheimer’s symptoms.
As Alzheimer’s progresses,
excessive amounts of glutamate
are produced in certain parts of
the brain, thus overstimulating
one class of glutamate
receptors, the NMDA receptors,
and making the glutamate toxic
to the neurons.
Memantine acts as an NMDA-receptor
antagonist, taking the place of
glutamate and thus reducing the toxic
effects that glutamate has when it is in
excess. Memantine is generally well
tolerated; its undesirable side effects
(dizziness, headaches, etc.) are
reported by fewer than 10% of all
patients.
Amyloid beta
Amyloidogenic processing of amyloid precursor
protein (APP) by BACE1 and g-secretase. The
figure depicts the principal proteolytic
processing steps of APP leading to the
production of 40–42-residue amyloid b (Ab)
peptide, the subsequent steps ultimately
culminating in compaction and deposition of
the peptide in b-amyloid plaques in brain of AD
patients (and transgenic AD mouse models),
and the primary point of intervention by the
different therapeutic antiamyloid approaches.
Future treatments now being
developed for Alzheimer’s target
the beta-amyloid peptide that is
responsible for senile plaques
and the tau protein that is the
source of neurofibrillary tangles.
Researchers are trying to block
the harmful effects attributed to
beta-amyloid by inhibiting its
formation, by breaking down
amyloid plaques that have
already formed, and by
modifying the abnormal form of
the tau protein.
One approach being explored for
breaking plaques down is
immunotherapy, in other words,
a vaccine against Alzheimer’s.
Research is being done on two
different forms of vaccination:
active and passive.
In active vaccination, Alzheimer’s
patients are injected with an
antigen so that their immune
systems start to produce
antibodies that attack the
amyloid plaques.
In passive vaccination, the
antibody against beta-amyloid
is injected directly.
In 1999, active vaccination was
shown to be effective in
transgenic mice. After
vaccination, these mice
produced antibodies against
the beta-amyloid peptide, had
lower levels of beta-amyloid in
their blood, and showed
improved cognitive function.
The first human trials of this
vaccine began in 2001 but
were discontinued one year
later because of serious side
effects (encephalitis) in 18
of the 300 subjects who had
been vaccinated (6%).
Follow-up showed that in
some of these subjects,
there was a decrease in
amyloid deposits together
with modest improvement
in cognitive function.
One example of research on passive
vaccination was a set of clinical
trials conducted in 2008 with the
monoclonal antibody
bapineuzumab, which binds
specifically to the beta-amyloid
protein. Here too, a slight
improvement in symptoms was
observed, but with some significant
side effects.
Tau
• Possible tau-based therapeutic strategi
es in Alzheimer disease.
A loss of tau function might be overcome with
microtubule-stabilizing agents or inhibitors of tau
hyperphosphorylation and/or acetylation. Potentially
toxic tau oligomers or fibrils might be prevented by
inhibitors of tau multimeric assembly. Inhibition of
HSP90 and the resulting elevation of the chaperones
HSP70/HSP40 may increase proteasomal degradation
of hyperphosphorylated tau. Misfolded tau multimers
might be cleared through enhancement of
macroautophagy.
Finally, misfolded tau species may be released from
cells and internalized by nearby neurons, thereby
“seeding” the formation of pathological tau in the
recipient cell. If confirmed, this spreading of tau
pathology might be inhibited by antibodies that bind
misfolded tau in the brain interstitial fluid.
To block the build-up of
defective tau proteins in the
neurons, the most promising
drugs involve two well known
compounds that have been
used in medications for many
years.
The first of these drugs is
methylthioninium chloride
(commonly known as methylene
blue), a molecule first
synthesized in 1876 and used
since then to treat malaria,
urinary infections, and many
other conditions.
In clinical trials, methylene blue appeared
to stabilize the cognitive decline of 321
subjects in the early to middle stages of
Alzheimer’s. After 19 months of taking a
moderate dose three times per day, the
subjects in the active-drug group had
still shown no further decline, whereas
in the placebo-drug group, the subjects’
decline had continued.
Moreover, brain imaging showed
that in some of the subjects’
brains, this drug had been
active in the areas where
defective tau proteins were
most abundant.
The second of these drugs,
latrepirdine, was originally
developed and marketed as an
antihistamine in Russia. It has
many chemical properties and
appears to have a beneficial
effect on the mitochondria of
the neurons of people with
Alzheimer’s.
A trial involving Russian subjects with
Alzheimer’s, published in the
medical journal The Lancet in 2008,
showed that, compared with
members of the placebo-drug
group, members of the group that
received latrepirdine showed better
memory and fewer behavioral
problems.
But the results of a Phase 3
clinical trial involving patients in
North America, South America,
and Europe, published early in
2010, did not show the same
effectiveness.
Though these results are
disappointing, they do not
necessarily mean that latrepirdine
will not eventually be recognized as
effective. That is what happened
with memantine, for which some
trials also produced negative
results.
The US Food and Drug
Administration (FDA), the body that
approves drugs for use in the
United States, will generally grant
approval when two-thirds of the
results are positive.
Researchers are exploring many
ways to try to find medications
for Alzheimer’—for example,
any drug that could improve the
effectiveness of a certain type
of microglia that can effectively
eliminate amyloid plaques.
But in addition to medications,
there are a wide variety of
“complementary", nonmedical therapies that can
improve or slow the progress
of certain symptoms.
Many of these therapies
attempt to stimulate
patients’ remaining
faculties so as to improve
wellness and quality of life.
One example is cognitive
remediation, a computerassisted therapy that stimulates
abilities needed to perform
activities of daily life—abilities
such as attention, memory,
language, and hand-eye coordination.
Another is
reminiscence therapy, which
uses items such as
photographs and music to
evoke memories from
Alzheimer’s patients’ past
and get them to talk about it.
Still another therapy uses
multiple sensory experiences
in a peaceful setting to
improve Alzheimer’s patients’
mood while reducing
agitation and apathy.
Other approaches are
based on using art, music,
pets, and other methods
to provide emotional
stimulus.
•
To date, research on vitamins (B,
C, and E) and other substances
such as ginkgo biloba, folic acid,
and selenium has not provided
any conclusive evidence that
they are effective in preventing
Alzheimer’s or slowing its
progress.
(however see Preventing Alzheimer’s disease-related gray
matter atrophy by B-vitamin treatment PNAS 23 110 (23) 9523-9528.)