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Hope for Alzheimers?

MagazineApril 2009 (Vol. 20 Issue 1)Hope for Alzheimers?

Stand by for a battle-royal over Alzheimer's disease (AD)-to take place in

Stand by for a battle-royal over Alzheimer's disease (AD)-to take place inthe British High Courts of Justice, no less. Shortly,

in a unique court case, NICE (National Institute for Clinical Excellence), the UK's National Health Service drugs watchdog, will be challenged to defend its decision not to fund Alzheimer's drugs intended for use in the early stages of the disease.

Ranged on the prosecution benches will be two big guns of the pharma-ceutical industry, Pfizer and its marketing arm Eisai, aided and abetted by the Alzheimer's Society, a vociferous patient support group that equally loudly proclaims itself to have no ties with any drug manufacturers.

What's all the fuss about? Are the Alzheimer's drugs any good at all, and are there any alternatives? And what causes the disease in the first place?

Dementia and Alzheimer's

From near-obscurity only a generation ago, Alzheimer's disease is now probably, after cancer, the most feared disease of old age. Alzheimer's has been chillingly described as an affliction whose victims suffer theloss of qualities that define human existence.

Once considered a rare disorder, it is now known to be the most common type of senile dementia, defined as physical damage to the brain in old age that results in major changes to reasoning, memory, personality and behaviour. Until recently, the only way to distinguish Alzheimer's from other types of dementia was by post-mortem examination of the brain. A typical AD brain is found to be partly atrophied, with the brain cells clumped together in what are called 'neurofibrillary tangles' or 'plaques'.

The second major type of dementia is vascular dementia, where the interruption of the brain's blood supply, usually due to 'mini-strokes', causes brain cells to die.

These two main types of dementia can now sometimes be distinguished from each other by brain scans using either magnetic resonance imaging (MRI) or positron-emission tomog-raphy (PET).

Senile dementia is not as inevitable as many people might imagine: between 25 and 50 per cent of individuals over 85 are spared it. Nevertheless, dementia is on the increase, so the drug companies claim, because of the simple fact that we're

all living longer. It is believed to be incurable.

Big Pharma's offerings

Any prolonged chronic illness that is only ended by death is, of course, meat and drink to the pharmaceutical industry. And yet, perhaps surprisingly, there are relatively few drug treat-ments available for Alzheimer's. First on the market was tacrine (marketed as Cognex) in 1993. Like virtually allof its successors, tacrine is a so-called cholinesterase inhibitor, which acts by artificially maintaining levels of acetyl-choline in the brain. This important brain chemical is known to be reduced by as much as 90 per cent in AD sufferers; it's also believed to be important for memory, so finding a drug that can preserve the chemical in the brain makes sense.

In fact, the theory is fine-the trouble is the side-effects. After just a decade on the market, tacrine began to be no longer actively marketed after reports of severe liver toxicity. As much as 60 per cent of patients found the drug's side-effects to be intolerable at high doses. The final nail in tacrine's coffin was that, after all this, it really doesn't work (JAMA, 1998; 280: 1777-82).

Since then, three other drugs have come onto the market, all of which attempt to do the same trick of increasing acetylcholine in the brain. As expected, these drugs are all deadly rivals. Pfizer's Aricept (donepezil), has an advertising tagline that says 'when Alzheimer's hits home, Aricept can help'; Novartis' Exelon (rivastigmine) claims to be 'another step forward against Alzheimer's disease'; and Shire Pharmaceuticals/Janssen's Reminyl (galantamine) sells itself with the somewhat vague tagline 'Reminyl is now'.

So far, Pfizer is the only manu-facturer to have threatened a lawsuit against the recent NICE ruling that none of these drugs is really worth taking in the early stages of AD. Will the drugmaker win their case? Our prediction is no-and, frankly, because the evidence is stacked against them.

The only large-scale, truly indepen-dent clinical trial of Pfizer's Aricept was carried out by a team of British researchers at the University of Birmingham. In a double-blind trial that lasted for more than two years, Aricept was tested head-to-head against a placebo in over 500 patients who had mild-to-moderate AD.

The study's conclusions? Aricept works, but its benefits are very small-"below minimally relevant thresholds" (Lancet, 2004; 363: 2105-15). As study director Professor Richard Grey stated in the report: "Patients and their families would probably notice no difference if the drug was stopped."

What's more, even clinical trials funded by the drug companies them-selves failed to show much benefit with any of their products. For example, Oxford University researchers recently scrutinized data from 24 separate Pfizer-sponsored Aricept trials, involv-ing more than 5000 patients at different stages of AD, and concluded that "the treatment effects are small and are not always apparent in practice". Add to that the strong likelihood of "many adverse events" such as nausea, vomiting, diarrhoea, muscle cramps, dizziness, fatigue and anorexia, and it's little wonder that there's what the researchers politely refer to as a "debate" over whether Aricept is worth a candle (Cochrane Database Syst Rev, 2006; 1: CD001190).

The same Oxford scientists have also examined another of Pfizer's claims-which is also supported by the strictly independent Alzheimer's Society-that Aricept helps prevent the onset of AD, stopping what is classified as 'mild cognitive impairment' (MCI) from turning into full-blown Alz-heimer's. The researchers' conclusion? According to their report: "There is no evidence to support the use of Aricept for patients with MCI. The putative benefits are minor, short-lived and associated with significant side effects" (Cochrane Database Syst Rev, 2006; 3: CD006104).

What of Aricept's two other rivals, however? Again, independent studies of the clinical data have exposed the drug companies' marketing hype.

With MCI, for example, Polish researchers concluded earlier this year that the efficacy of all three cholinesterase-blocking drugs was "questionable", especially given the high incidence of side-effects, some of which-as in the case of Reminyl-apparently can be fatal (Neurol Neurochir Pol, 2007; 41: 13-21).

As for full-blown AD itself, three groups of independent researchers all agree that the three drugs, although having slightly different modes of action, all produce broadly similar effects-or rather, a lack of effects. Their benefit to Alzheimer patients

is variously described as "not large" (Cochrane Database Syst Rev, 2006; 1: CD005593), "limited" (Tijdschr Psychiatr, 2006; 48: 17-26) and "small" (Drugs Aging, 2007; 24: 155-67).

Nevertheless, Aricept remains the market leader in a highly profitable$3 billion a year business that is fore-casted to grow exponentially.

But there's one new drug that is beginning to challenge Aricept. It's called memantine (marketed as Ebixa, Axura, Namenda and Akatinol). Strictly speaking, it's not a drug, as it's derived from the naturally occurring mineral adamantine, and it also works in a different way from its pharmaceutical rivals. Developed by Merz, a German manufacturer of natural health products, the compound appears to protect brain cells against glutamate, the amino acid that is thought to be toxic to the brain in excess amounts and to trigger Alzheimer's.

Clinical trials of memantine have been promising, showing it to be particularly effective in moderate-to-severe AD, although it generally only slows mental decline rather than reverses it (Drugs, 2006; 66: 1515-34). Detailed testing has found that it appears to benefit attention and nformation-processing speed more than memory (Int J Geriatr Psychiatry, 2006; Nov 20; epub ahead of print).

Its side-effects are hardly greater than a placebo tablet, with a slight tendency to produce tiredness and dizziness. It is widely used in Germany, often in preference to the standard drugs; however, in Britain, it is still considered experimental.

Alternative treatments

Meanwhile, gradually emerging into the limelight are a number of promising plant-based treatments, some of which turn out to have properties that seem almost tailor-made for AD.

Take the humble culinary sage plant, Salvia officinalis. In addition to having potent antioxidant and anti-inflammatory effects, sage is known to have anticholinergic effects similar to Aricept's. When tested against placebo in a recent clinical trial, 60 drops of sage oil a day was often found to be better than Aricept at maintaining mental functioning in people with mild-to-moderate AD-and without any side-effects (J Clin Pharm Ther, 2003;

28: 53-9). Sage oil can also improve memory in younger people, too.

Lemon balm (Melissa officinalis) has been found to bind to the brain receptors believed to be involved with anxiety, thus reducing the agitation symptoms seen with AD. Particular strains of the plant have also proved able to slow the decline of mental functioning (Curr Pharm Des, 2006; 12: 4613-23). However, although some proponents recommend these plants as aromatherapy for Alzheimer sufferers, the evidence is considered "inconclu-sive" (Aust NZ J Psychiatry, 1999; 33: 789-99).

The classic herbal memory-enhancer is Ginkgo biloba, which has been proven in numerous clinical trials to benefit mental faculties in people of all ages. Germany is where it's most used for Alzheimer's, as even German conventional doctors consider it prefer-able to the pharmaceutical drugs on offer.

Although it's by no means a miracle-worker, Ginkgo has been shown to benefit virtually all AD patients to some degree, and about a third of them quite significantly. The recommended dosage is 240 mg/day of the Ginkgo extract codenamed 'EGb 761'; the benefits normally show up within six months (Pharmacopsychiatry, 2003; 36: 297-303). It's even been suggested that Ginkgo might help prevent the onsetof AD but, so far, no research has been done to test its possible role in Alzheimer's prevention.

What of the other 'smart drugs' that are sometimes claimed to be memory-enhancers for the able-bodied? Of these, only nicergoline (derived from ergot) appears to have any evidence of benefit, with up to a threefold improvement on some performance measures in AD (Cochrane Database Syst Rev, 2001; 4: CD003159). Vinpocetine and piracetam, although better known, don't appear to have been adequately tested in Alzheimer's patients to come to any firm conclusions.

On the near horizon, the curry spice curcumin is being investigated as a potential anti-AD compound, after it was recognized that people in India have lower rates of the disease. Lab tests by neurologists at UCLA have already shown that curcumin can repair brain cells damaged by AD, and clinical trials are currently underway(J Alzheimers Dis, 2006; 10: 1-7).

Traditional Chinese medicine offers two sets of herbal mixtures: Yi-GanSan is a combination of seven different plants, headed by angelica root; andBa Wei Di Huang Wan (BDW) com-prises eight herbs, including cinnamon and peony. Initial research shows that they may be useful in AD (Evidence-Based Complement Altern Med, 2006; 3: 441-5).

There is currently excitement over one Chinese herb in particular, a rare club moss called Huperzia serrata.

Five years ago, an extract of the moss-huperzine alpha (Hup-A)-was tested in more than 200 Chinese diagnosed with mild-to-moderate AD. The results were described as "remarkable". After taking 400 mcg of Hup-A for less than three months, 60 per cent of the patients were observed to be "clinically on the mend". Only about a quarter of patients failed to respond. Side-effects were "mild and transient" and, in any case, affected very few of the patients (Zhonghua Yi Xue Za Zhi, 2002; 82: 941-4).

How does Hup-A work? It's thought to increase acetylcholine levels in the brain. But, in fact, it's much better than that. It penetrates the brain more effectively than the current drugs, and lasts longer. It also has a wider range of effects, including protecting cells against further damage from inflam-mation and oxidation (Acta Pharmacol Sin, 2006; 27: 1-26). Here again, a clinical trial is currently ongoing.The Chinese also use acupuncture for Alzheimer's, and there is evidence that it may work (Zhongguo Zhen Jiu, 2005; 25: 390-2). In a Westernized varia-tion of this, doctors have tested TENS (transcutaneous electrical nerve stim-ulation) therapy. Applied to various parts of the body (even the face), TENS has been shown to have some value, particularly in the early stages of AD. However, according to the Japanese doctors using it, the therapy needs to be repeated to sustain benefits beyond six months (Front Med Biol Eng, 2002; 11: 237-47).

Hopeful horizons

One possible AD treatment is chelation therapy. Often derided as mere quack-ery, chelation has been used for decades by frontier-spirited cardiol-ogists to combat heart disease. The treatment involves transfusing a chemical cocktail into the bloodstream that will bind itself to harmful agents and carry them away. Chelation's earliest use was to remove toxic levels of lead from workers in the battery and paint industries, but it's now finding a revival in Alzheimer's patients.

The argument is this: if metal toxicity is involved in AD (see box, page 8), then chelation may be able to bind and flush away the harmful metals before they can cause brain damage.

One of the first trials of chelation used clioquinol as the chelating agent. The results were promising, showing a slight clinical improvement after three weeks (Dement Geriatr Cogn Disord, 2001;

12: 408-14). However, the results of the only subsequent trial were less encouraging (Cochrane Database Syst Rev, 2006; 1: CD005380).

Despite these disappointing find-ings, a whole slew of researchers across the globe-from Osaka University to Harvard-are actively pursuing the chelation route in hopes of making a breakthrough. Some scientists are even suggesting using 'nanoparticles' to trick the brain into allowing more powerful chelating agents past its barriers (Neurosci Lett, 2006; 406: 189-93).

The fact that researchers are being forced to consider such high-tech solutions says two things: the existing treatments aren't working; and Alzheimer's may be a rather tougher nut to crack than we thought.

Tony Edwards

AD symptoms and risks

In its early stages, Alzheimer's disease (AD) can be difficult to distinguish from the usual memory loss, the 'mild cognitive impairment' that often arises in old age and causes those classic 'senior moments'.

Other conditions that can be confused with AD are a thyroid imbalance, vitamin-B deficiency, brain injury or tumour, severe depression and drug side-effects.

Major warning signs of Alzheimer's disease

- Memory loss severe enough to affect job or life skills

- Difficulty performing familiar tasks

- Language problems

- Disorientation (of time and place)

- Poor or decreased judgement

- Problems with abstract thinking (such as following directions)

- Misplacing things

- Changes in mood or behaviour

- Changes in personality

- Loss of initiative

- Repeating questions

- Getting lost in familiar places.

There is no set pattern to AD. It usually comes on gradually, unlike vascular dementia, which generally has a step-wise worsening (after each 'mini-stroke') and may involve mild paralysis or slurred speech.

AD is ultimately fatal, with death occurring an average of eight years after diagnosis. However, this figure can range from three to as many as 20 years.

But contrary to popular belief, Alzheimer's is by no means inevitable.

Who are most at risk?

- Women

People with:

- lower levels of education

- a significant family history of AD

- a history of head injury

- a BMI (body mass index) of under 20 or over 22.5

- Anyone over 65.

By age 65, roughly one in 14 people will have developed Alzheimer's; the risk doubles every five years from then onwards, tailing off at around age 85 (but only in men).

Causes of AD

Medicine is no less prey to fashion than any other branch of life. Twenty years ago, aluminium was thought to be the major cause of Alzheimer's disease (AD); 10 years ago, the idea was firmly pooh-poohed, but now it's back on the agenda again.

For this, we partly have to thank the French epidemiologists who performed a series of long-term surveys of the incidence of AD and drinking water. The biggest one was an eight-year study tracking the onset of dementia in everyone over the age of 65 in an area of southwest France. Within this general area, many local boroughs have their own water supplies.

What the researchers found seemed to be clear-cut. In the boroughswith relatively high levels of natural aluminium in the water (more than0.1 mg/L), there was a more than doubling of the number of AD cases(Am J Epidemiol, 2000; 152: 59-66).

However, the small print of the data wasn't quite as simple as that.

The same researchers had previously found that there were two other key factors, without which the aluminium-AD connection no longer showed up. One factor was the acidity of the water. In areas where the water was alkaline, aluminium had no effect. Equally, where there were high natural levels of silica in the water, high aluminium not only had no effect, but actually seemed to protect against AD (Epidemiology, 1996; 7: 281-5).

Given apparently paradoxical results like these, the fact that there's been so much to-ing and fro-ing over the dangers of aluminium is hardly surprising. Added to that, it's known that non-prescription antacids contain vastly more aluminium than any water supply does and, yet, chronicantacid addicts appear to be at no greater risk of developing Alzheimer's than anyone else (Regul Toxicol Pharmacol, 2001; 33: 66-79).

The current thinking is that aluminium in the water supply must be more easily taken up by the body (Brain Res Bull, 2001; 55: 187-96).

Aluminium is probably not the only metal to be involved in Alzheimer's. Copper, zinc and iron have also been fingered as possible culprits (J Biol Inorg Chem, 2004; 9: 954-60), as has mercury (see Viewpoint). In these cases, the evidence comes from either laboratory cell cultures, animal studies or autopsies of AD patients rather than from surveys of living people. Nevertheless, experts are becoming iconvinced that even small quantitiesof these four metals are involved in AD. The metals are thought to createan oxidative inflammatory response in the brain, causing the brain cells to clump into the disease's characteristic neural plaques (J Alzheimers Dis, 2004;6: 291-301).

The inflammation theory is further bolstered by the finding that AD sufferers tend to have high levels of homocysteine, a naturally occurring amino acid. It is best known as a marker for heart disease, but it's also believed to be toxic to brain cells, probably through an inflammatory mechanism (Am J Clin Nutr, 2005; 82: 636-43).

Preventing AD

- Drink wine regularly, but in moderation-it can halve your risk of Alzheimer's disease (AD). The data are less clear for beer, however (Neurology, 2002; 59: 1313-9).

- Coffee reduces AD risk by a third (Am J Epidemiol, 2002; 156: 445-53).

- Get your amalgam fillings removed. See The WDDTY Dental Handbook

for the correct procedure for having this done.

- Take a good selenium supplement. A nine-year study of over 1000 old people showed that those with the lowest selenium levels had the greatest "cognitive decline" (Epidemiology, 2007; 18: 52-8).

- Take an omega-3 supplement or eat fatty fish three times a week-both contain the essential fatty acid DHA (docosahexaenoic acid). A nine-year survey found that older people with relatively high DHA levels almost halve their risk of Alzheimer's (Arch Neurol, 2006; 63: 1545-50).

- Supplement with folic acid, or choose foods naturally high in folic acid, such as green, leafy vegetables. High folic-acid levels destroy harmful homocysteine, with clinical trials showing that high folate levels can halve

the risk of AD (Arch Neurol, 2007; 64: 86-92).

- Exercise regularly. Exercising three times a week reduces the risk of AD

by about 30 per cent, even if you're over 65 (Ann Intern Med, 2006; 144: 73-81).

- If you can't or don't feel like exercising, drink three glasses of fruit or vegetable juice a week. It can reduce your risk of AD threefold (Am J Med, 2006; 119: 751-9).

- Have your water supply checked for aluminium (it's a free service from your water provider). If it contains more than 0.1 mg/L of aluminium-and one study even suggests that 3.5 mcg/L can be a problem-and has a pH of less than 7, drink mineral water containing high levels of silica, which will neutralize the effects of the metal (Epidemiology, 1996; 7: 281-5).


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