2004-06-15
Simon Garfield

With 20 per cent of us facing Alzheimer's in old age, pharmaceutical companies are scrambling to find the magic pill that will halt or reverse, its devastating effects. Simon Garfield reports.

So a man goes to the doctor, and the doctor tells him there is bad news. In fact, there is bad news and really bad news. Which does he want first?

"The really bad news."

"The really bad news is that you have AIDS."

"Oh my God. And what's the bad news?"

"The bad news is you also have Alzheimer's."

"Could be worse," the man says. "At least I don't have AIDS!"

This year may be remembered as the year in which we all got the really bad news. Alzheimer's competes fiercely with HIV to be the disease of our times and it is difficult to get through a day without hearing someone say: "Now where did I put that thing — I must be getting Alzheimer's." The disease has entered our culture far beyond the level of dubious internet jokes.

One cannot imagine what it is like to have no memory. We may forget where we left our car, but we do not forget that it is somewhere in the car park.

Psychologists have long since tired of telling each other that we are our memories, but it is as potent a thought as ever. It is no wonder that severe memory loss can be a disaster for those who experience it and those who observe it.

Alzheimer's also affects the way we think about memory. Although it is only one of several diseases of dementia, its prevalence in an ageing population has turned the study of how we remember into a booming business just at the time when our anxiety about the effect of computers and mobiles on our ability to retain basic information has never been greater.

Until recently, memory loss was not considered a trait one could do much about. This is no longer the case. Our understanding of the way the brain functions with regard to memory has advanced rapidly and we are now able to pinpoint its decline and hint at its repair.

In a low white building in Irvine, California, about 90 minutes' drive from Los Angeles, Cortex Pharmaceuticals is a modest start-up company with 21 full-time staff and 48 patents. The patents describe compounds designed to treat several neurological and psychiatric disorders, including Alzheimer's.

Alzheimer's also affects the way we think about memory. Although it is only one of several diseases of dementia, its prevalence in an ageing population has turned the study of how we remember into a booming business.

The company used monkeys to test two compounds labelled CX516 and CX717. Known collectively as ampakines, they act on the predominant chemical neurotransmitter that plays a vital role in the exchange of information between cells and underpins the formation of many types of memory within the hippocampus, the site where short-term memories are converted into long-term memories. Ampakines are also thought to increase the strength of signals between brain cells at the very points of connection adversely affected by Alzheimer's.

Not that the monkeys cared about this. Their main incentive for the memory tests was a squirt of juice. The tests lasted for about 90 minutes, and six monkeys were used over several days. Their reaction time was monitored alongside their success rate and the results were measured against the varying strengths of the drugs administered before the test.

These figures were then compared with placebo trials. The success rate without the drugs was high: between 70 and 80 per cent of the objects were correctly identified. Even at low dosages, the intake of ampakines boosted performance markedly, and as the number of milligrams increased, so did the monkeys' hit rate.

But recently there was a setback. An international trial of 175 people with Mild Cognitive Impairment (MCI), a condition in which patients display serious but manageable levels of memory loss, and which is often a precursor of Alzheimer's, showed disappointing results: those taking CX516 performed no better in a 15-word test than those on the placebo.

Cortex put forward several reasons for this failure, claiming that the dosage of the compound was too weak and that it had a very short potency of under an hour. "We should have killed CX516 five years ago," a company spokesman tells me, in the same breath as he says that the latest compound, CX717, is designed to remain effective for 10 times longer, and is 50 times more powerful.

"The early results," he says, "make us very optimistic."

The board of directors at Cortex includes Carl W. Cotman, a professor at the University of California, Irvine, where he also runs the Institute for Brain Ageing and Dementia. Cotman is a great believer in the potential of ampakines, but he recently made headlines by showing that memory and cognitive function are quite capable of being boosted by substances you can already buy at the supermarket.

In February, he told the American Association for the Advancement of Science of his diet experiments with beagles. Dogs who had their normal meals laced with vitamins C and E and a nice selection of fruits and vegetables were compared to dogs who ate normal fare. Younger dogs on the special antioxidant diet showed no great improvement when challenged to distinguish the odd object in a group of similar ones, but the benefit to the older ones was unmistakable.

But should we be surprised that the factors that are well established in limiting the risks of heart disease can also have a beneficial effect on our memories?

Tanned and silver-haired at 63, Cotman works in an office strewn with copies of his own publications. He's an amiable man but there is no mistaking the frustration when he talks about the wider reaction to his work. He believes that the correct diet may delay the conversion of normal ageing to dementia by 20 or 30 per cent.

"The problem is, how do you prove it?" he says. "How the heck do you do a placebo-controlled diet study in which people get the same food for breakfast, lunch and dinner for two years? It ain't gonna happen."

He cites a recent study from the Mormon community in Cache County, Utah, which showed that a combination of vitamin A and C delayed the onset of Alzheimer's.

"Significantly — it almost halves it. You should say, 'Holy smoke!' But a lot of people don't believe it, because it's a survey and not placebo-controlled."

Cotman and colleagues have proposed an exhaustive clinical trial involving 4000 patients and lasting five years, but he fears the cost of about $US35 million ($A49 million) will be prohibitive. He also doubts whether funds will be made available to finance an irrefutable large-scale study to show that elderly people who are physically fit have less brain atrophy than those who take no exercise.

Human trials in those over 65 have shown that over a six-month period those who underwent aerobic walking for 45 minutes a day three times a week performed better on attentive and decision-making tests. Another experiment has suggested that exercise increases neurogenesis (new neuron formation).

"So good Lord," Cotman says. "I mean, what does it take to change people's habits?"

The basic knowledge of Alzheimer's was well established when Cotman began his work in the 1970s, but had advanced relatively slowly since Alois Alzheimer had first met his disorientated 51-year-old patient Auguste D in Frankfurt in 1901.

By the time she died in 1906, Dr Alzheimer had ruled out Parkinson's, Huntington's or schizophrenia, and when he examined her brain under a microscope he found something he had never before noticed in the cortex: a mass of brown spherical "plaques" obstructing communication between neurons, and a darker knotty string of "tangles" that choked neurons within their cells.

The formation of these plaques and tangles is part of the normal process of ageing and only becomes a problem when the proteins that form them — known as beta-amyloid and tau — are produced in excessive amounts.

While ampakines and other drugs target specific areas in the hippocampus, memory relies on several areas in the brain to function effectively. The frontal lobes draw on memory to make decisions and manage information, while the temporal lobe stores and processes past events, and MRI scans show the damage to these areas in Alzheimer's patients.

Recently, Nature published findings from two American studies that independently located for the first time the "penny-sized" area in the cortex responsible for the retention of all short-term memory; it was suggested that damage to this spot alone might have a huge impact on our cognitive abilities.

Drugs such as Aricept, Exelon and Reminyl work in a similar way to restrict an enzyme that blocks acetylcholine, essential for communication between neurons.

The newer drug Ebixa, which helps block the release of excessive glutamate that damages brain cells, appears to slow down the advance of Alzheimer's even in later stages. One day, there may be a vaccine. In the meantime, the best treatment will be combination therapy — a cocktail of drugs.

But a few weeks ago a dampener was cast over the efficacy of all the existing drugs at a conference at Johns Hopkins University, Baltimore, when a group of specialists at the Alzheimer's unit doubted whether they would cause any reduction in the huge increase of cases for decades.

"You can name 11 fruits in a minute instead of 10," said one professor. "Is that worth 0 a month?"

Reminyl was originally made from the bulbs of snowdrops and narcissi, one of many natural compounds believed to be beneficial to memory and cognition. The best known is extracted from the leaves of the ginkgo biloba tree, although the results of a large-scale American study released in 2002 suggested it had no effect on the memory of healthy older people.

Earlier this year, a small-scale study conducted in Edinburgh showed verbal memory improved significantly among men aged 55-75 given carbenoxolone, a compound based on liquorice root thought to block the production of the stress hormone cortisol.

Other indications suggest cholesterollowering statin drugs may help, as may oestrogen intake in post-menopausal women before Alzheimer's starts.

Huperzine, an alkaloid from a natural herb, has been used for centuries in China as an anti-ageing treatment and memory booster, and when tested in cell cultures was found to save cells from beta-amyloid degeneration.

From the earliest school exams onwards, memory has traditionally been about learning lists. There are spatial and olfactory techniques as well, but list-learning is still the fundamental way memory is tested and the clearest indicator that enhancement has worked.

Doctors apply a traditional list of questions, known as the Folstein Mini- Mental State Exam, to determine whether a patient may need a brain scan for Alzheimer’s, and psychologists employ traditional word lists — train, garden, table — to test their latest experiments.

Traditional and novel methods of memory enhancement can be found in a tall stack of books that rises by about a foot each year. Most rely on a combination of visualisation systems and mnemonics.

At the department of psychology at the University of Leeds, Chris Moulin and his colleagues are engaged in studies to repair learning in Alzheimer's patients without chemical intervention. They also use standard word lists, and some olfactory tests, as the main indication of the success of their inquiries.

I met Moulin at the university, where he admitted somewhat sheepishly that he collected shopping lists in an album, and told me that his fascination began after he found a list on the floor of a memory clinic that read "bin liners, memory clinic, lunch".

Moulin has conducted tests with Alzheimer's patients in which he has given them more time to learn things, and others in which he has consistently repeated words, but to little effect. Alzheimer's patients usually have little residual memory to work with.

"But this is now a happy story," Moulin says, confirming the effectiveness of a notion known as "errorless learning". This work, pioneered by Linda Clare and others at University College, London, works against the usual practice of learning by trial and error, and limits the mistakes one can make.

"It's so simple," Moulin says. "Initially I might say, 'I'm thinking of a word beginning with the letters wa' and you might get warmth, wagon or water. So I would say, 'No, it's wafer.' In the other scenario I would say, 'I'm thinking of a word beginning with wa and it's water.' So basic, but it can increase learning by 20 or 30 per cent."

This can't help recover memories that have already been lost, but it is an effective way of retraining those with a particular difficulty in remembering names and faces.

Happily, Moulin also notes that as we get older, our memory gets more positive. "A large proportion of people in their 30s will say they had a lousy childhood, but by the time the same group are in their 80s only about 5 per cent are still saying that," he says.

There is no question researchers like less than "How long until the cure?" There is no cure in sight; when pushed, the people at Cortex will express hopes of accessible and effective new treatments within five to 10 years, much too long for many.

They are more certain that the challenge of defining how and what we should remember in our lives is far greater than the solutions offered by even the smartest medical fixes or tests with lists.

- Observer

http://www.theage.com.au/articles/2004/06/14/1087065082699.html?from=moreStories