Tenuous and complex, half-submerged within the normal processes of aging, the mechanisms that drive neurodegenerative diseases such as Alzheimer’s and Parkinson’s have so far largely eluded the grasp of modern medical science. Specific treatments for these conditions exist, but are far from satisfactory, and none really does what a true anti-degenerative therapy should do—prevent disease from occurring in the first place.
Recent epidemiological studies, however, suggest that significant preventives of these diseases may be already at hand—and very familiar. Differences in diet and behavior that are good for us in other ways also turn out to be associated with big changes in risk for developing serious brain diseases.
Guided by these findings, researchers are beginning to uncover broad mechanisms of “neuroprotection” that may naturally delay age-related brain diseases in those who would otherwise succumb.
“It’s been estimated, for example, that if you could delay the age of onset of Alzheimer’s by five years, overall amongst the entire population, then you would reduce the prevalence of the disease by about 50 percent,” says Ranjan Duara, who studies neurodegenerative disease risk factors at the Mount Sinai Medical Center in Miami.
Drink moderately, stop smoking, lose weight
At the American Academy of Neurology’s annual conference in Chicago in April, Duara presented results from a study, conducted by his institute, of lifestyle factors in more than 600 people with Alzheimer’s disease. According to interviews with the patients’ relatives, subjects in the study who had been relatively heavy drinkers (more than two beers per day) when younger had developed Alzheimer’s almost five years earlier than fellow subjects with lighter drinking habits. The heavier smokers (more than a pack per day) had developed the disease about two years earlier than lighter smokers or non-smokers.
These numbers are merely averages among relatively small patient groups, but statistically they suggest that heavy drinking or heavy smoking is associated with a significantly earlier onset of Alzheimer’s, Duara says. “The apparent effect is comparable to that of the major genetic risk factor for late-onset Alzheimer’s,” he says, namely the ε4 allele of the apolipoprotein-E gene, which has also been linked to a greater risk of coronary heart disease.
“These effects came out as additive, too,” Duara says. “Which basically tells us that if you have a genetic risk factor already, then you need to be particularly vigilant about known risk factors for the disease that are modifiable. You can do something about factors that are lifestyle issues.”
At the same conference, and online March 26 in the journal Neurology, epidemiologists from the healthcare group Kaiser Permanente in California reported on a long-term study of nearly 10,000 men and women in northern California, stretching back to the 1960s. According to the study, those individuals with high blood cholesterol levels, obesity or large bellies when in their 40s were significantly more likely to develop Alzheimer’s later in life.
A study reported in the January issue of Movement Disorders by Harvard researchers found that among 143,325 people being tracked in a long study of nutrition and disease, the risk of Parkinson’s disease during the nine-year study window was moderately lower for those who reported being more physically active at the outset.
A much stronger association between exercise and neurodegenerative disease incidence was reported by Seattle clinicians in the Annals of Internal Medicine in 2006: When 1,740 older adults were followed for six years, those who at the outset had reported exercising more than three times per week showed a 40 percent lower incidence of Alzheimer’s than those who had reported exercising less.
The possibility exists that less exercise is associated with more disease simply because the disease process itself, in its early, pre-diagnosis stages, causes people to withdraw from physical activity. But there are good reasons to believe that exercise and lifestyle can be causative.
More exercise generally means healthier blood vessels and better blood flow, says Eric Larson, who led the 2006 study. “If you have a healthier blood supply to your brain, your ability to sustain insults is greater. And we think that vascular problems in the brain tend to reduce the brain’s ability to withstand stress—and the most sensitive part of the brain to vascular injury is the hippocampus, where memory resides and where Alzheimer’s changes typically start.”
University of Chicago neurologist Richard Kraig has been looking at other more direct neuroprotective mechanisms that may be enhanced when people exercise—and to Kraig even mental exercise qualifies.
“Increased social, intellectual and physical activity—so-called environmental enrichment—generates a brain that is more resistant to disease,” he says.
Kraig and his colleagues have found evidence suggesting that when neurons are active and firing, their activity triggers the release, by nearby microglial cells, of low levels of an immune chemical called tumor necrosis factor alpha (TNF-α).
Normally TNF-α in the brain is considered a marker of an inflammatory attack or major clean-up operation following infection or injury. When released in relatively large amounts by microglia, it helps to trigger an immunological cascade that can kill or wound every neuron in the vicinity.
In recent years, however, lab-dish and animal studies have shown that TNF-α, at concentrations thousands or millions of times lower than lethal, can somehow protect neurons from damage by certain toxins and injuries.
Kraig suspects that TNF-α’s seemingly dual nature reflects the principle of “what doesn’t kill you makes you stronger.” TNF-α serves as an irritant, causing neurons to increase their production of DNA-repair and nerve-growth factors that in turn help defend against injury.
Kraig says his lab also is looking at other factors, including diet and sleep, that might be able to boost neuroprotective levels of TNF-α in the brain.
Wake up, smell the neuroprotection
One dietary ingredient that has long stood out for its potential to prevent neurodegenerative disease is caffeine. Although epidemiological studies suggest that its protective effects against Alzheimer’s are modest at best, both epidemiological and animal studies have hinted that this ubiquitous drug could have a major effect in preventing Parkinson’s disease.
In 2000, researchers from the National Institutes of Health, the University of Hawaii and other centers reported in the Journal of the American Medical Association that in a large group of men enrolled in a long-term health study, more coffee-drinking was strongly associated with less chance of being diagnosed with Parkinson’s. Among those in the highest category of caffeine consumption, the incidence of Parkinson’s during the study period was less than one-fifth of that seen in the non-caffeine-drinking group
In humans, caffeine promotes wakefulness by blocking the brain-cell receptors for adenosine, an inhibitory neurotransmitter whose activity normally enforces drowsiness and sleep. Adenosine also normally inhibits the same motor neurons in the striatum region of the brain that are slowed in Parkinson’s disease. Studies in animal models of the disease have shown that by blocking striatal adenosine receptors, caffeine helps to keep those neurons active and healthy for longer.
Michael Schwarzschild, a research clinician at Harvard and Massachusetts General Hospital, notes that more specific adenosine-receptor blockers, known as A2A antagonists, have been developed by several drug companies and are now being tested in people who have Parkinson’s disease. Initially they are being tested to reduce the side-effects of standard dopamine-replacement therapy, but ultimately they could even be useful as first-line therapies that slow the disease process.
“I think basically that A2A antagonists are among the most promising and realistic new medication approaches for Parkinson’s,” says Schwarzschild.
On 15 April, the Archives of Neurology published online a study by Schwarzschild and his Harvard colleagues that highlights the potential of another diet-related factor as a neuroprotective in Parkinson’s. In a group of 804 Parkinson’s patients followed for about two years after their diagnosis, those with the highest levels of urate in their blood at diagnosis had on average a markedly slower progression of disease during the study period than those with the lowest urate levels. Urate is a form of uric acid, blood levels of which can be boosted by some foods and beverages, including liver, alcohol and some seafood.
“Urate has antioxidant properties, and also metal-binding properties,” says Schwarzschild. “Because oxidative damage and metal toxicity are both seen as possible contributors to the Parkinson’s disease process, a protective role of urate in Parkinson’s seems plausible.”
Unfortunately, although more than one study has hinted at urate’s neuroprotective properties, higher urate levels are also associated with a higher risk of gout, coronary heart disease, hypertension and stroke. A 2007 study in the journal Neuropsychology even linked higher uric acid levels to lower cognitive scores in the elderly.
Still, Schwarzschild hopes that, at the right levels, urate will slow the progression of Parkinson’s disease without causing unacceptable side effects. He and colleagues will soon begin tests with people who have been newly diagnosed with Parkinson’s of a urate precursor, the dietary supplement inosine, which has separately shown neuroprotective effects in animal models of stroke and spinal cord damage. Preliminary results are expected in 2010, Schwarzschild says.