*if you have trouble viewing this email, click here to view webpage: ADDF Newsletter Vol. Five- Fall 2009*

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.

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.

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."

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."

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.

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.
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.

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.

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?

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?
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.
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.
"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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