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| A prescient new test can "see"
the barest wispy beginnings
of Alzheimer's disease in
spinal fluid so well it can predict
which people with minor memory
problems will get the disease.
A University of Pennsylvania
team, led by pathologist Leslie Shaw,
accomplished this by running
cerebrospinal fluid through a device
that spies Alzheimer's-associated
proteins at barely detectable levels.
He found that patients with high
levels of one protein - tau -
and certain low levels of another
- amyloid-beta - developed
Alzheimer's a year later. Patients lacking
this protein pattern
did not -even
patients with
similar cognition
problems.
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The test may
someday let doctors
start preventive treatment
for Alzheimer's before the
disease manifests. It is cheap,
easily standardized and can
serve as a "biomarker" of disease
progression in the future, perhaps
as significantly as cholesterol does
for heart disease. The test could
monitor response to treatments in
clinical trials, and may help determine
if experimental Alzheimer's drugs
are "disease modifying", revealing
which robustly attack the disease
and which just alleviate symptoms.
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| Marsel Mesulam, MD, director
of Northwestern University's
Cognitive Neurology and Alzheimer’s
Disease Center, says more needs
to be known about the test's
potential. It has not yet been used
to distinguish Alzheimer's from
other dementias. "That is where
a lot of us clinicians desperately
need a biomarker," he notes.
Still it has excited many experts, including Mesulam. "It shows the
amyloid in cerebrospinal fluid gives
considerable information as a
biomarker for detecting Alzheimer's,
and for following its progression.
To have a biomarker sensitive to progression is very important."
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The study is one of the first
to emerge from the $60 million
Alzheimer's Disease Neuroimaging
Initiative (ADNI), the largest
Alzheimer's project ever funded by
the National Institutes of Health.
ADDF provided modest funding to
ADNI and ADDF's Dr. Howard Fillit
serves on its external advisory
board. Says ADNI consultant William Potter of Merck Research
Laboratories: "I am wildly
enthusiastic about the ADNI results
to date and am confident that much
more will emerge that can be tested
in subsequent studies." 
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| Alzheimer's is a disease in
which many channels in the
brain (called "pathways")
become blocked, or break down,
at once. Many different drugs may
thus be needed. An ingenious
scientist living in Israel has
concocted a single drug to halt the
breakdown of many channels at
once; to send a potent, special
"cocktail" of drugs - all stemming
from one easily ingested pill -
flowing through the troubled
tributaries of the Alzheimer's brain.
In the late 1970's, neurochemist
Moussa Youdim, PhD, interested in
"adventure," he says, moved to Israel from Oxford University to help the prestigious Technion Israel Institute of Technology launch its first pharmacology department.
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Once there, he approached Teva
Pharmaceuticals with an idea for
a new Parkinson's disease drug.
Teva, then a small generic drug
company, said no. But in 1987,
when Teva became the third largest
generic drug distributor in the US, it
changed its mind. Youdim's resulting
rasagiline was revealed, this
January, to slow Parkinson's
in patients so well
it may become
one of the first
Parkinson's drugs
to achieve the
FDA's coveted
"disease
modifying"
label.
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| It protects healthy neurons and may restore
sick neurons - an unusual feat.
Youdim found rasagiline was
active against Alzheimer's,
too. But
before even
offering it to
Alzheimer's
patients,
Youdim's
spirit of
adventure
moved him
again. Having
intensely studied
human brain genes, he
and a colleague were struck by the
fact that in many neurodegenerative
diseases, many channels of
communication breakdown or go
awry, seemingly at once. Like others
since, "We came to the conclusion
there would never be a magic bullet
for any of these diseases. We
needed a multifunctional drug that
could act on different sites in the
brain." So Youdim enthusiastically
began improving rasagiline before
he was even done clincally testing
the original. He mixed a key
ingredient in rasagaline with a key
ingredient of VK-28, an enzyme
that clears neural areas of harmful
iron build-up. The resulting "multimodal"
drug (called M30) is like the
multi-drug "cocktails" made famous
by AIDS - but it has been created
from only active ingredients of each
to form a single molecule.
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| The resulting multimodal
M30 protects healthy neurons
and restores dying ones in
animal models -again, an
exciting development on
its own, as an upcoming
Yodium paper in Neurotoxicity
Research will show. It looks promising as anti-depressant and an
anti-inflammatory, and slows both oxidative
stress and dangerous Alzheimer's-related
amyloid plaque build-up. It increases the
"neurotransmitters" that surge between
healthy neurons delivering information, and
that so catastrophically recede in
Alzheimer's. It may accomplish all this with fewer side
effects - at a lower cost - than multiple "whole" drug
cocktails. And the different key ingredients - called "moieties" -
act together in ways they don't as separate drugs.
Youdim, the Technion and the Weizman Institute of Science have
built a biotech called Varinel around multi-modal drugs, which aren't
necessarily unusually difficult to make, just the product of an unusually
open mind. Youdim jokes the idea came to him because he is in Israel.
"The beauty of being in Israel is that you are outside the rest of the
world so you can see it clearer." (Varinel was partially funded through
a Biotechnology Development grant from ADDF.) Dreamed up by a
perennially adventurous scientist, the futuresque chemical cocktail
M30 - along with others Youdim has concocted - may prove
potent for patients, indeed. For more information, please visit
www.varinel.com.
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Diabetics stand a 30 to 65%
higher risk of developing
Alzheimer's, many studies
have noted. Fascinatingly, there are
enzymes in the brain that latch onto,
and clear away, harmful Alzheimer's
proteins such as beta-amyloid.
These enzymes can also latch onto,
and get distracted by, insulin instead,
especially when there is excess
insulin. That is the case in Type 2
diabetes: there is often too much
insulin around. Could diabetes drugs
that lower insulin free up those
natural anti-Alzheimer's enzymes?
Could we combat Alzheimer's
and diabetes with a single drug?
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 | Jose Luchsinger, MD, MPh,
a Columbia University assistant
professor of medicine, is attempting
to launch this two-front war using
a single well-known weapon:
Metformin, the world's most popular diabetes drug. He is giving it to some
patients with amnesic mild cognitive
impairment-a pre-Alzheimer's
condition - in a Phase II clinical
trial funded by the National Institutes
of Health and the ADDF. Since
obesity increases the risk of both
diabetes and Alzheimer’s, all
patients in the study are overweight.
Will Metformin patients develop
Alzheimer's at a slower pace?
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| Insulin helps glucose enter
cells and is their primary source
of energy. Glucose is especially
critical in the brain, since neurons
are completely dependent on it for energy. Without glucose, or insulin,
people rapidly enter into a coma. In
obese people and those with Type 2
diabetes, the pancreas makes
excess insulin because the body's
cells don't respond, creating a
state of "insulin resistance." This
excess insulin can be deleterious.
In 2003, neuroscientist Suzanne
Craft, PhD, of the University of
Washington discovered that an
enzyme called "insulin degrading
enzyme" (IDE) clears out amyloidbeta
(which forms harmful
Alzheimer's plaque) from the brain,
but can be inhibited by insulin.
Luchsinger hopes that, by reducing
insulin resistance, Metformin will help
Alzheimer's patients by decreasing
insulin levels, freeing IDE to clear
out harmful amyloid beta, while
also improving glucose utilization
in the brain.
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 | Structure of
human insulin-degrading
enzyme (IDE) in complex with
beta-amyloid. The molecular surface of IDE
is represented by light yellow. The N- and
C-terminal domains of IDE are colored
green and red, respectively. The betaamyloid
(blue) is entrapped inside the
degradation chamber of the IDE molecule.
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"Metformin is widely regarded
as an effective drug with a very
good safety profile, says Luchsinger.
"It helps diabetes prevention in
many areas linked to Alzheimer's.
There is a good case it will be
beneficial." Stay tuned!
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