Panel: No magic bullet against Alzheimer's

BETHESDA, Md. — The scene was a kind of science court. On trial was the question "Can anything — running on a treadmill, eating more spinach, learning Arabic — prevent Alzheimer's disease or delay its progression?"

The National Institutes of Health (NIH) sponsored the court, appointing a jury of 15 medical scientists with no vested interests in Alzheimer's research. They would hear the evidence and reach a judgment on the data.

For a day and a half in the spring, researchers presented their cases, describing studies and explaining what they had hoped to show. The jury also heard from scientists from Duke University who had been commissioned to look at evidence — hundreds of research papers — and weigh it. And the jurors had read the papers, preparing for this day.

The studies included research on nearly everything proposed to prevent the disease: exercise, mental stimulation, healthful diet, social engagement, nutritional supplements, anti-inflammatory drugs or those that lower cholesterol or blood pressure, even the idea that people who marry or stay trim might be saved. And they included research on traits that might hasten Alzheimer's onset, such as not having much of an education or being a loner.

It is an issue that has taken on intense importance because scientists recently reported compelling evidence that two types of tests, PET scans of Alzheimer's plaque in the brain and tests of spinal fluid, can find signs of the disease years before people have symptoms. That gives rise to the question: What, if anything, can people do to prevent it?

The jury's verdict was depressing and distressing. Nothing has been found to prevent or delay the devastating disease, which ceaselessly kills brain cells, eventually leaving people mute, incontinent, unable to feed themselves, unaware of who they are or who their family and friends are.

"Currently," the panel wrote, "no evidence of even moderate scientific quality exists to support the association of any modifiable factor (such as nutritional supplements, herbal preparations, dietary factors, prescription or nonprescription drugs, social or economic factors, medical conditions, toxins or environmental exposures) with reduced risk of Alzheimer's disease."

"I was surprised and, at the same time, very sad" about the lack of evidence, said Dr. Martha Daviglus, the panel chairwoman and a professor of preventive medicine and medicine at the Feinberg School of Medicine at Northwestern University. "This is something that could happen to any of us, and yet we are at such a primitive state of research."

The state of the evidence reflects in part the long time it took before researchers even realized Alzheimer's was a disease, said Dr. Richard Hodes, director of the National Institute on Aging. Until the mid-1980s, many thought dementia was a normal part of aging, and so serious studies of its causes and prevention did not really begin until then. Scientists have spent the years since searching for factors that might affect risk, checking data from other studies to see if, for example, diet or blood pressure or years of education might be associated with the disease.

In the meantime, doctors are in a bind. Should they tell people to do things like walk briskly or eat vegetables, activities that might someday be shown to protect against Alzheimer's and that certainly cannot hurt? Or should they wait for absolute proof, confirmation that a diet or a drug or an exercise regimen prevents Alzheimer's?

The Alzheimer's Association tells people to exercise, challenge themselves mentally, remain socially engaged and keep their hearts healthy. Such measures can only help, said Dr. Maria Carrillo, a senior director of the organization.

But, she said, "The Alzheimer's Association certainly agrees that there is not enough evidence to say anything definitive about the prevention of Alzheimer's disease and any kind of intervention."

Hodes said there are many reasons to follow practices to improve general health. But, he said, researchers have to be careful about implying that any measures will protect against the degenerative brain disease. "We don't know that yet," Hodes said.

Problematic studies

Dr. John Williams Jr., head of the Duke group that evaluated the studies, expected relatively few studies and clear results.

To its great surprise, the Duke group discovered a vast amount of literature on Alzheimer's prevention. Instead of coming up empty on many topics, Williams said, "We came up empty on very few."

The problem, the group wrote, was "the quality of the evidence was typically low."

Most studies observed people who happened to use or not use a possible preventive measure and then determined whether they got Alzheimer's or not.

Such studies, known as observational ones, are not the gold standard, like those in which people are randomly assigned to take a pill or do something, such as exercise, or not. Observational studies are useful in generating hypotheses but are not proof. If several well-done studies of this type come to the same conclusion, they can be valuable evidence.

In the case of Alzheimer's prevention, though, the studies tended to have problems, Williams said.

Often it was not clear what subjects were doing. They might have been using a drug or a supplement at the start of the study but the dose was not specified, nor was it clear whether subjects were taking the same doses, or for how long.

Some studies of drugs to lower blood pressure used self-reports as opposed to, for example, pharmacy data. A 12-year study asked participants about their use of cholesterol-lowering statins at the start of the study but never did again. A nine-year statin study used pharmacy records but included as users those who took the drugs at any time during the study period.

Definitions of conditions, such as high blood pressure, tended to vary from study to study.

Descriptions of factors such as "strong social support" were vague or idiosyncratic. For example, some studies classified married people as having strong social support for that reason alone, with no evaluation of whether the marriage was good or bad.

Silent stalker

Looking over the piles of studies, the group rated evidence as high, moderate or low.

Low confidence did not necessarily mean the measures did not work; it meant the evidence was so faulty that there was no way of deciding.

In the end, the Duke group said it was highly confident in the findings for just one thing, the herb Ginkgo biloba. But in that case the evidence pointed in only one direction: It did not prevent Alzheimer's.

Moderate evidence, not totally convincing but not worthless, applied to only four factors studied.

Two were factors that increased risk. They were a particular gene, ApoE4, which, moderate evidence showed, increased risk about threefold, and menopause therapy with a combination of estrogens and progestins, which doubled risk.

The other moderate evidence indicated that certain things that had been hoped to be protective were not. For instance, there was moderate evidence that vitamin E, found in nuts, vegetable oils, green leafy vegetables and fortified cereals, had no effect on risk. There was also moderate evidence that cholinesterase inhibitors, drugs often used to treat Alzheimer's symptoms, had no effect.

Other than that, evidence was poor.

There is only poor evidence, for example, that keeping your brain active, having a high level of education or exercising has a protective effect. There is also only poor evidence that eating a Mediterranean diet — high in fruits and vegetables, fish and olive oil — will help stave off Alzheimer's.

There is only poor evidence that having poor social support or smoking increases risk.

High-quality studies of Alzheimer's will be difficult. Alzheimer's seems to progress silently in the brain for a decade before the earliest symptoms of memory problems surface. It can take another decade until the distinctive signs of Alzheimer's appear: profound memory loss and an inability to handle the normal activities of daily life such as bathing and dressing.

"Once there is even minimal cognitive impairment, the brain is damaged, inflamed, burning like a bonfire," said Dr. Caleb Finch, director of the Gerontology Research Institute at the University of Southern California.

As a result, high-quality studies of possible factors such as diet and exercise or mental stimulation before the disease's onset might have to last for decades.