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LIGHTS BACK ON?

New hope for dementia

by Rowan Hooper

In 1906, a German doctor called Alois Alzheimer discovered strange clumps in the brain of a woman who had died of a then-mysterious mental illness.

Nowadays, those clumps have become known as a hallmark of the incurable debilitating disease to which the doctor gave his name. Though researchers have identified the sticky protein plaques that form those clumps, they have yet to find a way to stop their buildup.

This week, however, they took a step closer to achieving that goal, with scientists reporting the action of an experimental drug that prevents plaque formation.

With 12 million Alzheimer’s disease sufferers worldwide (1.6 million of which are in Japan), no one is yet talking about a cure. However, the current breakthrough offers hope of developing treatment regimes for the sufferers’ slow slide into darkness as memories and mental faculties wink out one by one. As Nancy Reagan described it, her husband, seven years after his diagnosis, now sometimes picks up a model of the White House and stares at it, asking: “Has this got anything to do with me?”

As human life spans increase, this disease once regarded as rare is set to become ever more widespread and is predicted to affect some 14 million Americans over the next 50 years. In Japan, an epidemiological survey has predicted a steeper rise in Alzheimer’s than in other developed countries, as by 2020 a quarter of the population will be over 65.

There are numerous possible causes of Alzheimer’s — the commonest cause of dementia in old people — and there are probably multiple factors involved. Head injuries can increase the risk, which might be one of the reasons five-time world middleweight boxing champ Sugar Ray Robinson died with the disease. Pound-for-pound the greatest fighter of all time, he died knowing nothing of his achievements.

Certain infections and high-fat diets are also thought to increase the risk. Autopsies have shown aluminum and zinc in the brain cells of Alzheimer’s sufferers, but it is not known whether this is a cause or consequence of the disease. To further complicate the picture, people who regularly take nonsteroid pain relievers like ibuprofen are known to have a lower risk of developing the disease — and we haven’t even mentioned the genetic dimension yet.

Alzheimer’s sometimes strikes early in life, and this form often runs in families. Geneticists found that in cases of familial Alzheimer’s, there are mutant forms of genes responsible for the production of proteins called presenilins. Mutations in these genes lead to increased production of beta amyloid.

Beta amyloid is made by healthy cells, but in Alzheimer’s, too much of the protein is produced. It is thought to damage the brain in two ways. First, it is oxidative, meaning it produces free radicals of oxygen that are toxic to brain cells. Second, when too much amyloid is secreted, it builds up in plaques on the surface of brain cells. This can trigger an immune response that destroys brain cells — and hence wipes out memories.

People with the gene mutations that lead to increased output of beta amyloid will almost certainly know they have them, as they will have seen their parents succumb to the disease at anywhere between 30 and 50 years of age. And, unlike some of the other genes linked to Alzheimer’s, a person with one of these mutations will almost certainly develop dementia early on in life. Genes on chromosomes 10 and 21 seem particularly important in this respect.

Based on these understandings, Karen Shaw and colleagues at Baltimore’s National Institute on Aging tested an experimental drug, phenserine, in a growth medium containing human brain cells to try to to block the production of amyloids in the first place.

As reported in Tuesday’s edition of the U.S. journal Proceedings of the National Academy of Science, they found that the drug prevented the production of beta amyloid by reducing the production of one of its precursors. In so doing, they found, it was able to stop the amyloid production line before the critical point.

Phenserine is now undergoing clinical trials on human volunteers, and the hope is that it will lead to targeted treatment regimes for Alzheimer’s.

The news will be welcome in Japan, which will have 5.2 million bedridden elderly by 2025. But before such treatment starts, the Alzheimer Association of Japan would like to see other changes in the way patients are treated here.

In Japan patients are often restrained in some way — from being locked in their rooms to having their hands and feet strapped to their beds. In an AAJ survey in 1998, 50.9 percent of people caring for an Alzheimer’s sufferer said they thought such restraints were “unavoidable” and 27 percent did not think them necessary. While the AAJ recognizes that hospitals and nursing homes are understaffed, and acknowledges the problem of “wandering” patients, it regards such restraints as violations of human rights.

The most that the families of patients in Japan can look forward to at the moment is a better level of care, since Alzheimer’s disease has been incurable since its discovery. But the new work offers hope that the lights will stay on longer in the brains of future sufferers.