Alamy

BETA or tau? That is the question. On it hang both the health of many of the baby-boomer generation as they reluctantly stare old age in the face and the financial health of rich countries' medical and social-security systems. For, as the 10th International Conference on Alzheimer's Disease and Related Disorders, held recently in Madrid, heard, the relentless growth in the number of people with Alzheimer's threatens health-care provision in the developed world.

Medical advance means that other diseases are failing to cull the population before Alzheimer's destroys people's minds. And Alzheimer's is both expensive and lingering. In America, the average cost of looking after someone with the disease between diagnosis and death is at least $174,000.

At the moment, 4.5m Americans have Alzheimer's. By 2050, if nothing changes, that number will have trebled. But if a treatment that delayed the disease's onset by seven years were to be available by the end of the decade, the number of sufferers would decline by 40% by the middle of the century. Hence the importance of understanding how Alzheimer's works, the better to devise a treatment.

Beta (in the form of beta-amyloid plaques) and tau (in the form of tau tangles) are the physical manifestations of Alzheimer's. The plaques are globs of rogue protein in the spaces between nerve cells. The tangles are made of a different rogue protein, and form inside nerve cells.

The smart money says that plaque formation triggers the disease, and that the tangles are a secondary effect. This is known as the amyloid-cascade hypothesis, and most searches for treatment are based on it. But there are dissenters who reckon that this is the wrong conclusion. Some think that the role of the tangles is being underplayed, others that something altogether different has gone wrong.





It's all Greek

Amyloid plaques form when a molecule called amyloid precursor protein (APP) is chopped up by two enzymes known as beta-secretase and gamma-secretase. One of the products, with the long-winded name amyloid beta-peptide 42, has the unfortunate property that its molecules like to stick to each other. The resulting plaques, reckon supporters of the cascade theory, trigger the brain damage that manifests itself as memory loss, behavioural and personality changes, and general and irreversible cognitive decline. So, stop the plaques forming—or get rid of them once they have formed—and you should be able to control the disease.

One way to do so might be to develop a vaccine that stimulates antibodies against amyloid beta-peptide 42. That is the path being pursued by Elan Pharmaceuticals and Wyeth Research. In 2000, these two firms began a clinical trial of such a vaccine. Unfortunately, they had to halt it when 18 of the 300 patients involved developed severe inflammation of the brain. In the time that the trial had run, however, the researchers noticed that those patients who had reacted to the vaccine, but whose brains had not swollen up, showed a marked slowing of cognitive decline. This suggested they were on the right track, and the companies are now testing what they hope is a less toxic vaccine.

An alternative to vaccination is to make the antibodies in a factory, and then inject them. This is called passive immunisation. Preliminary trials suggest it is safe, and a study carried out by Wyeth showed that treatment with a single dose of antibody produced significant cognitive improvements over the course of four months. In other words, the drug does not just slow the disease, it reverses it.

Nor is the immunological approach the only one under investigation. For the past decade there has been a lot of work on drugs called secretase inhibitors, which alter the activity of the enzymes that create amyloid beta-peptide 42.

Researchers have known for some time that the long-term use of aspirin and ibuprofen, which belong to a group of drugs called non-steroidal anti-inflammatories, roughly halves a person's risk of developing Alzheimer's. This has nothing to do with their anti-inflammatory properties, though. It is because they also act on gamma-secretase. They alter the way it cleaves amyloid precursor protein. Instead of producing amyloid beta-peptide 42 (so called because it has 42 of the amino-acid units of which proteins are composed), they make peptides 37 or 38 amino acids long. These do not stick to one another.

Kenton Zavitz and his colleagues at Myriad Genetics presented the firm's latest findings on a non-steroidal anti-inflammatory derivative called R-flurbiprofen. Like many other molecules, flurbiprofen has a left-handed and a right-handed form. Normally, when the drug is synthesised, these are made in equal numbers. But it is possible to separate them.

Right-handed flurbiprofen lacks the anti-inflammatory effects of the left-handed version. This means it is less likely to cause the gastrointestinal problems associated with non-steroidal anti-inflammatories, so it is safe for long-term use. It still retains its APP-cleaving properties, though. The results of a trial with 200 Alzheimer's patients are encouraging. Patients with a mild version of the disease who took a high dose of the drug had a slower rate of decline than those who did not.





Hedging bets

Not everybody believes that focusing on amyloid is the right way to go, however. That is because there is, in fact, no clear correlation between the deposition of the plaques and the development of cognitive problems. Some dissenters think that tau tangles play a more central role than the cascaders have been willing to admit. There are also those, like Larry Goldstein, a professor of cellular and molecular medicine at the University of California, San Diego, who believe the triggering event is unrelated to either beta or tau, and is, in fact, a defect in the way that materials are transported through the filamentary protrusions, known as axons, that connect nerve cells to each other in the brain and to other cells a long way away in the body.

For tau, at least one drug is being tried out. Memantine has been prescribed for more than 20 years for various brain disorders, including dementia, because it is believed to protect against high levels of a neurotransmitter called glutamate. But there is evidence from several animal studies that it also prevents the modification of tau protein that leads to the formation of intracellular tangles. Work by Malin Gunnarsson and her colleagues at Uppsala University in Sweden recently confirmed that this is true in people, too.

Such bet-hedging is sensible. Alois Alzheimer's original paper, identifying both plaques and tangles, was presented in November 1906. A century later, the disease that bears his name is still a mystery—as is the question of how to treat it.