The search for new drugs that can reverse the course of Alzheimer's has frustrated pharmaceutical companies, with several failures reported in recent years. Research advances have arrived, not in the form of new drugs but, rather, in technologies that track the underlying biology of the disease before the first symptoms appear.
The capacity to track things early underlines the growing recognition that the disease process begins many years before a diagnosis, a realization that has placed new emphasis on the need for preventive measures to ward off the leading cause of dementia.
Unfortunately, this understanding cannot immediately be translated into a series of recommendations that a 50- or 60-year-old can adopt with reasonable certainty to fend off Alzheimer's. In late April a panel of experts convened by the National Institutes of Health (NIH), including gerontologists, nutritionists, neurologists and geneticists, found that various postulated approaches to prevention, ranging from use of prescription drugs, dietary supplements and avoidance of toxins, have "no evidence considered to be of even moderate scientific quality" to back recommendations that these steps can be used to stop the onset of the disease. The panel called for more studies that can identify risk factors by tracking large groups over a lifetime, similar to the famed Framingham study, and also gold-standard, "randomized" clinical trials that test subjects pursuing a particular preventive approach against those in a placebo group.
The panel's negative assessment on immediate prospects for prevention did not sit well with the Alzheimer's Association and some researchers, who stress the need for preventive strategies based on early, although not definitive, studies that point to benefits from steps related to diet, physical activity (anything from bicycling to housework) and other lifestyle measures. Maria Carrillo, senior director of medical and scientific relations for the Alzheimer's Association, criticized the way the panel considered the evidence for physical exercise as a preventive measure, excluding certain preliminary studies that clearly suggest staying physically active maintains healthy brain functioning and may help reduce the risk of Alzheimer's. "The Association expressed concern about the study’s negative tone and conclusions," she says. "We look at the evidence as the glass being half full, not half empty."
Other well-established investigators echoed Carrillo's misgivings. "We do have some ideas about interventions that make sense and are safe," says Kenneth Kosik, a researcher at the University of California, Santa Barbara, and founder of Cognitive Fitness & Innovative Therapies (CFIT), which counsels people on strategies to prevent dementia. "It's beyond me to understand why anyone would not want to endorse such ideas as long as we are honest and we tell people what the caveats are. Not doing anything for people at high risk is just being nihilistic"
A number of measures seem to defend against dementia in epidemiological and animal studies, although, as the NIH panel judged, the evidence may not suffice to make specific health recommendations "Our work and the work of others have converged on the point that exercise literally rejuvenates the aging brain," says Carl Cotman of the University of California, Irvine, who has demonstrated dramatic results regarding the benefits of physical activity in mice genetically engineered to develop Alzheimer's-like pathology. Cotman presented a summary of research on the potential of exercise for Alzheimer's prevention to the NIH panel.
Randomized trials to study the effectiveness of exercise or another intervention present multiple challenges to researchers because they are likely to last many years, much longer than a trial to test whether a drug, say, succeeds in shrinking a tumor. Drug companies are uninterested in funding trials on exercise or on whether an unpatentable natural substance like green tea might stop accumulations of the aberrant protein fragments involved in the underlying disease process. "Do these lifestyle interventions…—the green tea, the blueberries, the Mediterranean diet, fish, the omega 3s—do they truly reduce risk and prevent Alzheimer's disease?" asks Marwan Sabbagh, director of clinical research for the Banner Sun Health Research Institute. "It's going to take a lot of time and public funds in controlled clinical trials to answer some of these questions."
In a few cases randomized trials have tried to look at specific prevention measures. A small, randomized control trial reported last year by researchers at the University of Washington School of Medicine and the Veterans Affairs Medical Center in Seattle showed that sedentary adults with memory problems who were enrolled in a six-month exercise program improved in their ability to concentrate and carry out a variety of complex tasks compared with a control group that only completed stretching activities during the same period.
The trial illustrates the challenges of doing high-quality, randomized studies to look at the health impact of particular behaviors. The researchers took painstaking steps to structure the study to ensure that any differences between groups resulted only from the types of activities that each group completed. "When I see a difference, it's not just because one group was moving around a little more or one group was getting more attention from a staff member or one group was getting more experience at taking the test, because both groups were treated identically," says U.W. Medicine investigator Laura Baker. "Now we have a lot more confidence that the improvements we saw in thinking ability were caused by increased aerobic exercise and not other influences that could conceivably effect a change."
Finding innovative ways to examine the complex tapestry of diet and behavioral factors—even in the absence of the most rigorous trials—may prove instrumental in identifying components of a prevention strategy. A few clinical trials of vitamin E failed to show any benefit in preventing or treating Alzheimer's. But recent epidemiological studies have cast a wider net by looking at not just one dietary element but at the combination of nutrients furnished in the cornucopia of fruits, vegetables and healthy fats (think olive oil) furnished by the Mediterranean diet. Nikolaos Scarmeas of Columbia University Medical Center and colleagues found that subjects who hewed most closely to a Mediterranean-like diet (the study was conducted among residents of upper Manhattan) experienced a substantially lower risk of Alzheimer's.
Disentangling any specific ingredient that helps to stave off disease may prove impossible, but the interaction of plant chemicals from tomatoes, broccoli, carrots and red wine, among others, has started to intrigue the research community. "I believe and many researchers believe that these dietary patterns are important, not one single vitamin," says Miia Kivipelto, a professor at the Karolinska Institute in Stockholm.
Other investigators advocate an even more back to basics strategy. Karen Hsiao Ashe at the University of Minnesota came up with genetically engineered mice in the mid-1990s that produce the nominally toxic beta-amyloid protein fragments found in the brains of Alzheimer's patients, although the mice did not demonstrate the loss of brain cells that leads to dementia.
Later experiments convinced Ashe that the mice modeled not the loss of cognition but rather the disease development process before symptoms begin. As such, the rodents, she thinks, might prove ideal in testing the potential for prevention of a cocktail of natural compounds—from curcumin (an ingredient in curries) and omega-3 fatty acids from fish oils—substances that might be safe and inexpensive enough to ingest years before symptoms appear.
Ashe has worked with a husband and wife team from the University of California, Los Angeles, Greg Cole and Sally Frautschy, to devise different mixes that can be fed to the short-lived mice to determine whether they prevent a buildup of amyloid before symptoms appear, the period when these interventions are most likely to be effective. "The analogy I like to make to people," Cole says, "is that if you want to test the efficacy of brushing your teeth on people who need root canal, you'd prove that it was useless."
Prevention research will inevitably produce false starts: A randomized clinical trial last year that involved 3,000 people ranging in age from 72 to 96 found that the ginkgo biloba herb had no benefit in preventing cognitive decline. And a BBC-sponsored trial of brain games designed to improve mental function demonstrated that among 11,000 people between the ages of 18 and 60 players improved at playing the games themselves over time but did not enhance general cognitive skills.
Even so, the feeling of powerlessness before the specter of dementia has driven many people at risk to take steps, even in the absence of hard evidence. Bob Unruhe, an 86-year-old former president of the Los Angeles teacher's union, makes the trek once a week from the hills of his home in Ojai, Calif., to engage in training sessions that might consist of a round of a mentally challenging game like Mancala or balancing on a virtual ball on a Wii Fit at CFIT in Santa Barbara, the "cognitive shop" started by Kosik.
Unruhe felt his own cognitive abilities diminishing somewhat after caring for his wife, Virginia, who has had Alzheimer's for seven years. "I can sense my memory fading a little bit and I have a little more trouble searching for words and remembering names. So I'm trying to slow the aging process," he says of his decision to adopt CFIT's brain-healthy prescriptions, which include mentally challenging games.
The signal advance in the field—the advent of tools that enable the disease process to be tracked before symptoms appear—may help test new preventives in humans, not just in mice. Biomarkers that measure accumulation of aberrant proteins in the brain may reveal whether or not extracts from wine or curry are having an effect and may ultimately allow health authorities to formulate a specific set of recommendations in the same way as the American Heart Association sets out steps to fend off coronary artery disease.