Marching to Dementia

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by Bill Sardi

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The recent failure of an Alzheimer's drug trial threatens to leave the world with no effective remedies to head off an explosive increase in the numbers of people affected by this disease. By the year 2040 there may be as many as 80 million human zombies on the planet, adults who have lost their memory, ability to communicate, make judgments and live independently.

Recognizing humanity is running out of time, that the lengthening lifespans across the globe will surely increase the incidence of Alzheimer's dementia, drug companies have stepped up their research and development programs in hopes of reaping huge financial rewards. But sadly their efforts have fizzled.

Two major drug trials were in the research and development pipeline but one was just nixed off the list when the drug (bapineuzumab) was withdrawn from further human study by its pharmaceutical sponsors. That leaves another similar drug (solanezumab) as possibly the last hope for millions of senior adults suffering from this debilitating brain disease. Data will soon be announced on this drug, but this author doesn't give it much hope, as it is a monoclonal antibody drug in the same class as the failed bapineuzumab.

Still other researchers hold out hope for solanezumab saying it has a good safety profile so far in Phase II studies among Alzheimer's patients and favorably alters cerebrospinal and blood plasma markers. But altering markers is a long way from heading off this slowly progressive disease.

Have to diagnose it first

Even if a drug is proven to be effective in heading off the progression of the disease, modern medicine first has to agree upon an early pre-disease marker (a blood test most likely) that can be quantified.

Barnabas Wilson, writing from the Department of Pharmaceutics, Dayananda Sagar College of Pharmacy, in Bangalore, India, says:

"The major problem with Alzheimer's disease is its diagnosis. Even though magnetic resonance imaging, positron emission tomography, single positron emission computerized tomography, spinal fluid biochemistry and other laboratory tests are helpful to identify and study disease progression, a simple and effective diagnostic test is required to identify the disease at an early stage of disease progression. Lack of awareness results in low rates of recognition of disease by family members and physicians… Reportedly, the rates of such failure to recognize cases are 97% for mild Alzheimer's disease and 50% for moderate Alzheimer's disease."

Researchers have recently identified four blood markers (TNF (tumor necrosis factor), apolipoprotein E, C-reactive protein and B-type natriuretic peptide) as possible blood tests that could be employed to identify patients with the earlier signs of the disease.

Modern medicine currently prescribes ineffective drugs

Because of desperate pleas from families of loved ones affected by this brain disease, physicians often pacify their patients and prescribe ineffective drugs. While it is widely reported that "there are no medicines on the market that slow the progression of the disease," the pharmaceutical industry sells millions of dollars of ineffective drugs for use among Alzheimer's patients, an enzyme (acetycholinesterase) inhibitor being the most commonly prescribed.

(Let's see if health reform is going to put a halt to these ineffectual drugs and trigger a public upheaval that will likely end up parading Alzheimer's patients and their families before Congress in hearings to decide if withholding these drugs represents rationing.)

A European drug journal has just announced the French Pharmaco-economic Committee has downgraded existing drugs (Aricept, Namenda, Exelon, Razadyne and Cognex) prescribed for Alzheimer's patients, saying "they are best avoided and have no therapeutic advantage."

But wait, there is another drug

John Gever, writing at Med Page Today, says with children of Alzheimer's disease patients clamoring for a drug, in this case a drug that is already FDA approved but for another condition entirely (cutaneous T-cell lymphoma), puts physicians in an awkward position. The drug is bexarotene. When bexarotene was used among laboratory mice genetically bred to develop amyloid plaque in their brains. It astonishingly reduced the plaques by 50% within 72 hours. While other drugs have been successful in animal models of Alzheimer's disease, they have failed in human trials, including one of the recent drugs (bapineuzumab) where a human trial was halted.

But while Gregory Jicha MD, PhD, at the University of Kentucky at Lexington, says bexarotene should not be prescribed until tested "with appropriate safety oversight," he also says "the impetus to do something is quite high." But the true safety profile of FDA approved drugs is not even known till they are put into use in large groups. Late safety data is what brought the recalls of drugs like Vioxx. And bexarotene is already known to have a host of adverse effects which includes liver damage, pancreatitis, hypothyroidism, leukopenia (low white blood cell count) and elevated cholesterol. This sounds like disease substitution, not disease prevention. But the question arises, will physicians begin to prescribe bexarotene for off label use?

Researchers at the National Institutes of Health (NIH), writing in the New England Journal of Medicine, have dropped the idea that any promising small group study using bexarotene among patients with early Alzheimer's might prompt families of affected loved ones to beg their doctors for this drug. Sudden overwhelming pleas to do something by family members may be difficult for politicians to deal with and they might exert pressure to prescribe. The NIH researchers say "the early promise of bexarotene in a mouse model of Alzheimer's disease is exciting."

But why have NIH researchers chosen bexarotene over many other promising molecules, most of them being dietary supplements? Why not off-label use of dietary supplements for Alzheimer's disease. The pro-drug lobby can't say these natural remedies are unproven because neither are the drugs. In fact, some have been disproven but millions of dollars of these ineffective pills are still prescribed. There is at least as much scientific evidence for dietary supplements as remedies for Alzheimer's disease as there is for bexarotene, so why aren't NIH researchers "excited" about them?

For example, there may be as much evidence that an East Indian herb quells Alzheimer's disease as there is for bexarotene. A promising study with an East Indian herb, ashwaganda, reversed behavioral changes and brain plaque accumulation in the brains of middle-aged and old mice that were bred to develop Alzheimer's disease.

There is reasonable evidence to suggest supplemental melatonin may be helpful for Alzheimer's patients.

Thiamin (vitamin B1), given in its more absorbable form (benfotiamine), is said to exhibit "powerful effects" in improving mental function of laboratory animals in a model of Alzheimer's disease. Researchers are practically begging the National Institutes of Health to launch a study of vitamin B1 for Alzheimer's disease.

Special precaution

Researchers have already employed fairly high-dose antioxidants (vitamin E, vitamin C, lipoic acid, coenzyme Q10) among subjects with mild to moderate Alzheimer's disease, but these appeared to accelerate mental decline over a period of 16 weeks even though a marker of oxidation declined in cerebrospinal fluid. Markers of tau protein and beta amyloid did not decline with use of this antioxidant cocktail. The relative high dosage of antioxidant used in this study may be the problem here.

Estrogen to the rescue?

If female mammals have their estrogen-producing ovaries removed they develop problems with thinking and memory. If estrogen is replaced, learning and memory improves in animals.

Short-term use of estrogen has been shown to improve measures of attention, orientation, mood and social interaction among women with Alzheimer's disease. But the Women's Health Initiative study, published in 2002, horrified menopausal women as they learned their hormone pills might increase their risk for breast cancer, Alzheimer's disease and stroke. But upon careful re-examination, researchers report that the recommendation to back away from estrogen replacement was based upon “findings reported in press releases and interviews of the principal investigators that were often distorted, oversimplified, or wrong.” Why have American women been unduly frightened away from estrogen replacement?

Soy, as a weak plant estrogen, shows promise as an alternative to estrogen in the prevention and treatment of Alzheimer's disease.

And who knows, maybe we shouldn't be solely looking toward pills to remedy this disease.

But does beta amyloid brain plaque define the disease?

Drugs like bapineuzumab and solanezumab are designed to halt the accumulation of a cholesterol-like plaque called beta amyloid in the brain. But the whole idea of inhibiting beta amyloid buildup in the brain is being called into question. Ryan McBride, writing at FierceBiotech.com, says "many industry watchers have been left scratching their heads over the utility of attacking beta amyloid." Matthew Herper, medical writer for Forbes Magazine, says "skeptics don't believe the basic theory behind bapineuzumab, that plaques of a chemical are a cause of Alzheimer's, are true."

What modern medicine should be studying are the cases of minimal brain plaque that have been confirmed among a few centenarians. It is possible to live 100+ years and not be senile. Documentation is found here and here. What is striking is that neither the number of surviving brain cells (neurons) nor volume of amyloid brain plaque is significantly related to the clinical dementia rating that geriatricians use to measure severity of Alzheimer's disease in these centenarians.

Of particular interest is the red wine molecule resveratrol, which does not inhibit or block the production of beta amyloid like the failed monoclonal antibody drugs that modern pharmacology has fabricated, but rather works to degrade beta amyloid and assist in its exit (efflux) from the brain. One report written over a decade ago said "neuronal cell death due to oxidized brain lipids (fats) could be ameliorated by resveratrol, a polyphenolic compound known for its antioxidant properties." The toxic form of beta amyloid plaque that is described as a powerful neuron killing machine is inhibited by resveratrol.

Need for anotechnology questioned

A drug must cross the blood–brain barrier to exhibit therapeutic activity.

The idea of employing minified molecules within the range of 1 to 100 nanometers (one billionth of a meter) has been facilitate passage of drugs across the blood-brain barrier. Only a few attempts have been made to deliver anti-Alzheimer's drugs into the brain using nanoparticles.

Cells can absorb particles with a size less than 100 nanometers (billionth of a meter) in one dimension. Brain cells are capable of delivering drugs at the cellular and molecular level to treat brain diseases using nano-medicine.

Many small natural molecules from botanical sources are naturally nano-sized and do not require nano-sizing by man. Included in a list of naturally nano-sized molecules that may have application for Alzheimer's disease are the following:

Naturally Nano-Sized Molecules With Potential Application For Alzheimer's Disease

Natural Molecule

Avg size in nanometers

Natural source

Reference to Alzheimer's disease

EGCG

260

Green tea

J Molecular Biology 2012 Aug 24

Curcumin

45-80

Turmeric spice

Expert Opinion Inv Drugs August 2012

Ellagic acid

30

Pomegranate

Biochem Biophys Res Comm Dec 2009

Ferulic acid

100-200

Fruits

Neuroscience Letters Jan 2008

Quercetin

50-270

Onions, apple peel

Internatl Review Neurobiology 2012

Resveratrol

78180

Grapes, wine

Current Pharmaceutical Research 2012

Source: Biochemical Pharmacology 80 (12): 1833-43, Dec. 2010

A very intriguing natural molecule, founds in miniscule amounts in tea leaves and apple peel known as 7,8-dihydroxyflavone has gained considerable attention in the past two years for its ability to mimic something called brain-derived neurotrophic factor (BDNF). So far, BDNF has reversed experimentally-induced memory loss in the animal lab.

BDNF itself is not stable and can't cross the blood-brain barrier, a defense against toxins entering the brain, so it cannot be employed. But 7,8-dihydroxyflavone can pass through the blood-brain barrier. It is also known to produce an anti-depressant effect.

A problem is that 7,8-dihydroxyflavone is currently not available as a dietary supplement ingredient and would likely have to be synthetically re-produced.

However, resveratrol (rez-vair-ah-troll), known as a red wine molecule, is widely available and has been demonstrated to promote the natural production of BDNF in a laboratory dish and in lab animals. As an aside, BDNF also inhibits food consumption and may be a welcome mechanism for controlling obesity. Obesity is in fact linked to Alzheimer's disease. Bariatric (weight-loss) surgery for obesity has been demonstrated to produce better cognition (thinking).

Additionally, physical exercise has been shown to elevate the production of BDNF and physical exercise has been found to be somewhat beneficial among Alzheimer's subjects. The link between BDNF and exercise in Alzheimer's disease has been intensely explored.

The problem with resveratrol is that researchers falsely believe it is not bioavailable and cannot traverse the blood-brain barrier. To penetrate the blood-brain barrier molecules must be below about 500 Daltons in molecular weight. Resveratrol has a molecular weight of 228 Daltons and should readily enter the brain. Other similar-sized red wine molecules have been demonstrated to pass through brain capillaries grown in a lab dish. More intriguingly, a resveratrol-based dietary supplement has been demonstrated to resolve human cases of retinal disease (wet macular degeneration) and thus pass through the blood-ocular barrier, so these and other similar molecules must be passing into the brain.

Furthermore, Dr Edward Tobinick says drugs do not have to pass through the blood-brain barrier per se but send cellular signals via intermediary cells (tancytes) that contact the cerebrospinal fluid. So Alzheimer's drugs need not work directly upon the contact points (synapses) of adjoining brain cells (neurons). Dr. Tobinick says this challenges the dogma that penetration of a drug through the blood-brain barrier is necessary to produce rapid clinical effects

On an encouraging note, a human study of resveratrol will soon begin among patients with early-stage Alzheimer's disease. But researchers have decided to employ what may be a toxic high-dose of resveratrol, under the false assumption more is needed to get a little bit into the brain. These mega-doses of resveratrol may doom the molecule forever. Measured low doses of resveratrol activate a gene transcription factor known as Nrf2 which stimulates the natural activity of enzymatic antioxidants glutathione, catalase, superoxide dismutase and heme oxygenase. One would get the impression researchers are intentionally trying to doom this promising natural molecule that has already produced health benefits for humans in two trials. You can read the whole worrisome story about the upcoming resveratrol/Alzheimer's study here.

Bill Sardi [send him mail] is a frequent writer on health and political topics. His health writings can be found at www.naturalhealthlibrarian.com. His latest book is Downsizing Your Body.

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