Use it or lose it?

There seems to be mounting evidence that a lifetime of learning, mental and physical activity, and rewarding work is good for people. That finding also appears to be true when it comes to warding off Alzheimer's disease.

Although the disease seems to strike all socioeconomic levels at about the same rate, people with higher education, higher occupational status and even more participation in leisure activities seem to be able to keep the symptoms at bay longest. They appear to have what researchers have begun calling cognitive or brain "reserve" that allows them to compensate for the ravages inflicted on their brains by Alzheimer's disease.

Neuropsychologists, along with teams of neurologists, neuroscientists, behavioral neurologists and other medical researchers are beginning to piece together data that point to the idea that keeping the brain active and stimulated may reduce the risk of Alzheimer's disease.

"Some people--who are better educated, more active in work and leisure activities--seem to hold off developing the symptoms of Alzheimer's disease longer, despite having the same brain pathology as those who show symptoms earlier," says Columbia University neuropsychologist Yaakov Stern, PhD.

Defining terminology

When people think of Alzheimer's disease, they think of the clinical symptoms: memory loss, confusion and a gradual decline in all types of cognitive function. But the actual disease is characterized by a specific type of brain pathology: plaques and tangles that eat away at the brain, typically beginning with the hippocampus and areas involved in memory and later attacking the cerebral cortex, particularly circuits involved in language and reasoning. That's why Alzheimer's can't be officially diagnosed until death and autopsy. Before that, people are diagnosed with "probable Alzheimer's disease"--a diagnosis that is up to 90 percent accurate when performed by well-trained professionals.

The distinction between symptomology and pathology is important when it comes to discussing cognitive reserve because the theory hinges on the idea that people can have the pathology of Alzheimer's without showing clinical symptoms--at least for a while.

"Alzheimer's disease is a clinical entity that we know results from specific pathology," says Stern. "But there is not a direct one-to-one relationship between the pathology and how people present clinically. In other words, people can have the same pathology but present different clinically."

How is this possible? One theory is that these people have more neurons to lose. To test that, some researchers are now looking at brain size and how it correlates with developing the symptoms of Alzheimer's. But the most attention has hinged around the idea that some people can cope better than others with Alzheimer's pathology: They have more brain or cognitive reserve with which to compensate. What that "reserve" is remains up for grabs but it could mean people have neural circuits strong enough to withstand a certain amount of damage before giving out or that they have the ability to switch to unscathed neural circuits to perform tasks previously performed with now-damaged circuits.

Active brain, healthy mind?

Several paths of study have ingratiated this theory to researchers. For one, a growing group of epidemiological studies--many conducted by Stern and his colleagues--find that older people with less education, lower occupational status and fewer leisure activities are more likely to develop the clinical symptoms of Alzheimer's disease.

It's still unclear whether higher education itself helps create cognitive reserve, whether actively using your brain is the key or whether certain people are simply born with more cognitive reserve and it's these people who tend to become well-educated and hold higher status jobs. But several recent studies indicate a little bit of each.

For example, a study of Swedish twins published last year in Journals of Gerontology: Series B: Psychological Sciences & Social Sciences (Vol. 56B, No. 5) indicates that genetically endowed intellectual capacity might be the key. Researchers led by University of Southern California psychologist Margaret Gatz, PhD, found that level of education predicted Alzheimer's disease when looking at the study population as a whole, but not when they compared twins--one of whom had dementia and one of whom was healthy--against each other.

Rather than education, the researchers suggest that it might be intellectual involvement that provides protection from the symptoms of Alzheimer's. A new study published in the Feb. 13 Journal of the American Medical Association by researchers at the Rush Alzheimer's Disease Center at Rush-Presbyterian-St. Luke's Medical Center in Chicago supports that view. They found that participating in cognitively stimulating tasks reduced the risk of developing the symptoms of Alzheimer's disease among a group of 801 older Catholic nuns, priests and brothers participating in Rush's ongoing "religious orders" study. Since most study participants had very high levels of education, the researchers were able to remove that as a factor in their analyses.

On enrollment in the study, the researchers asked study participants--none of whom showed signs of dementia--how often they engaged in seven simple but cognitively stimulating activities: viewing television, listening to radio, reading newspapers, reading magazines, reading books, going to museums and playing games such as cards, checkers, crosswords or other puzzles. They found that the more cognitively active study participants were, the less likely they were to develop the symptoms of Alzheimer's disease. In fact, participants who scored in the top 10 percent on the cognitive activity scale were 47 percent less likely to develop Alzheimer's disease than people who scored in the bottom 10 percent.

"The effect of [cognitive activity] was pretty substantial," says neuropsychologist Robert S. Wilson, PhD, one of the study's lead investigators. "It strongly suggests that frequent participation in cognitively stimulating activities helps reduce the risk of Alzheimer's disease."

This finding concurs with that of Stern and his colleagues that decreased risk of Alzheimer's disease correlated with higher participation in leisure activities (Neurology, Vol. 57, No. 12).

But these studies don't answer the question of why. Wilson hopes that further data from the participants in the religious orders study will begin to do just that. Indeed, they already have autopsy results from 90 percent of deceased study participants. With those they can begin to examine whether cognitive activity reduces disease risk by a direct effect on Alzheimer's disease pathology or through some other mechanism such as an association with neuron numbers or synaptic density in brain regions critical for thinking and memory.

"It could be that having more neurons in a given area or more connections between the neurons makes that neuronal system less vulnerable to Alzheimer's pathology," he says. "Or it could have to do with brain plasticity--the idea that some people still retain plasticity by seeking new information or manipulating new information. There are many open possibilities."

Overwhelmed by pathology

A new, paradoxical finding adds to the epidemiological findings that increased mental activity reduces risk of developing symptoms of Alzheimer's disease: Once people with higher education or occupational status begin to show symptoms of Alzheimer's disease, their memories deteriorate far faster than those with less education and lower occupational status. They also die sooner.

Columbia's Stern and his colleagues found this trend when they matched Alzheimer's patients based on the severity of their symptoms and then followed them over time. This finding makes sense if you believe the theory that people with higher education or occupational status are merely compensating for the disease, not preventing it altogether, says Stern. In this scenario, the disease has to be quite well-advanced before these people begin showing clinical symptoms.

"People with higher education and occupational status already have more pathology [when they start exhibiting symptoms]," says Stern. "So they can cope to a certain extent but at some point [the disease] is going to overwhelm them."

In other words, their brains give out all at once rather than more gradually, as it appears to do in people with less cognitive reserve.

Of course, many researchers will point out that much of this theorizing is pure speculation. No one has done the definitive study to show that patients with higher education, higher occupational status or generally more active brains live symptom-free while Alzheimer's pathology eats away at their brains. Nor have they found that they tend to have more brain pathology than patients with similar symptoms but lower education, worse jobs or less active brains. Indeed, such a study is difficult to design since brain pathology can only be measured at autopsy.

That said, Stern and his colleagues as well as several other groups have done some studies using brain scanning techniques that tend to support the cognitive reserve theory. They've used scanning techniques that measure blood flow in the brain--such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). The idea is that blood flow measured in the brain when it's resting--that is, inactive--decreases over time in areas where Alzheimer's pathology exists.

In their study, Stern and his colleagues scanned the brains of patients matched for clinical severity and compared brain blood flow with educational status and occupational attainment. Those with higher education and occupational status showed signs of worse pathology. Gene Alexander, PhD, of Arizona State University found similar findings using literacy scores rather than education or occupation, and Stern and his colleagues have a study submitted for publication finding the same for leisure activities.

"These findings go along with our thoughts about epidemiology to support the idea of cognitive reserve," says Stern.

He's also looking for evidence that people with Alzheimer's disease begin to compensate for damage caused by plaques and tangles. In their only published study in this area, they used PET to compare which parts of the brain people use to do a simple word-matching task. They compared a group of healthy older people with a group of older people diagnosed with probable Alzheimer's disease and found that while some of the Alzheimer's patients used the same neural network as the healthy elders, some used a different network.

"They were still able to perform the task but they used a different network to do it," said Stern.

Elusive answers

Despite the intriguing evidence pointing to the idea that some people have cognitive reserve that protects them, at least for a while, from the symptoms of Alzheimer's disease, many researchers remain skeptical. Most of the evidence is still correlational and many questions remain, including the mechanism by which education or cognitive activity might provide protection.

"I think the key to understanding this concept is that it's not at all clear whether various indicators of cognitive activity are concomitant with reduced risk of Alzheimer's disease or whether they're simply indicators of overall better cognitive health," says Bill Thies, PhD, vice president for medical and scientific affairs at the Alzheimer's Association in Chicago.

Indeed, people with better education, better jobs and who are more cognitively active might simply have lived healthier lives.

Unfortunately, it will likely be difficult to ever know with certainty whether being more cognitively active will help people stave off Alzheimer's, adds Thies. Studies of interventions aimed at increasing cognitive activity will be extremely difficult to do. They'd need to be quite large, there's no way to blind participants to which intervention they're in and ensuring that people comply with the intervention would be nearly impossible.

"People won't hurry off to do those trials," says Thies. "With that said, there's probably lots of good reasons to recommend to people that they cultivate habits of healthy aging, including keeping active, physically, mentally and socially."