Experimental Alzheimer's drugs have been racking up one clinical trial failure after another in recent years. At the same time, evidence has building in favor of low-cost pharma-free strategies, at least as preventives. Getting regular exercise, avoiding obesity and diabetes, sticking to a healthy, perhaps Mediterranean or intermittent-fasting diet, and staying active socially and intellectually-all these now seem promising as Alzheimer's risk reducers and/or delayers of cognitive aging in general.
Another approach that has been attracting a surprising amount of scientific attention lately is "having a higher purpose in life." Also known as "eudaimonic well being," it isn't really a strategy per se. One can't just take it up as easily as one can take up jogging or yoga. But it is a psychological factor that seems linked to major health benefits, including protection against cognitive decline.
"Purpose in life seems to protect against the risk of developing Alzheimer's disease and other, milder forms of cognitive impairment, and appears to help older people maintain cognition even when they have some of the hallmark changes of Alzheimer's in their brains," says Patricia A. Boyle, a researcher at Rush University Medical Center in Chicago.
Scientists naturally would like to know how that works-and how to extend the same benefits to everyone, not just those who are fortunate enough to have a sense of purpose.
Purpose and cognitive health
It has long been part of physicians' folklore that people with a positive, purpose-driven outlook on life are relatively resistant to disease as well as hardships in general. Neurologist and psychiatrist Viktor Frankl, who was held in German concentration camps during World War II, famously "observed that those with a sense of meaning in life were better able to cope with the horrific circumstances in the camps," says Boyle.
Recently she and her colleagues set out to determine whether purpose in life could be tied scientifically to health benefits. In one study, which began about a decade ago as part of a larger study known as the Rush Memory and Aging Project, she and her colleagues followed the cognitive health of 900 elderly people in the Chicago area for seven years. At the study's outset, the researchers gave each person a questionnaire designed to gauge his or her level of purpose-driven-ness-defined by the researchers as "the tendency to derive meaning from life's experiences and to possess a sense of intentionality and goal directedness that guides behavior." At the end of the study, the scientists calculated that the people scoring initially in the top 10% on the purpose-driven measure were about 2.5 times more likely not to have been diagnosed with Alzheimer's during the study window, compared with those in the bottom 10%. This was the case after the researchers had corrected for depressive symptoms, undiagnosed Alzheimer's, and several other potentially confounding differences between the groups.
The researchers found that these more purpose-driven subjects also were about 50% more likely to have avoided MCI (mild cognitive impairment), an intermediate state of memory decline that frequently leads to Alzheimer's. In addition, the same group exhibited (on average) a slower rate of age-related cognitive decline.
Boyle and her colleagues followed up with a study, published last year, in which they autopsied 246 of the subjects who had died. They found that having a higher purpose in life at the study outset was associated not with fewer signs of Alzheimer's type brain pathology, but with a more moderate cognitive impact of that pathology. "Purpose seems to help older people maintain cognition even if they have some of the hallmark changes of Alzheimer's in their brains; that's pretty remarkable," says Boyle.
Understanding the connection
It's important to remember that these were not experimental studies, in which two groups are randomized to a "treatment" or "placebo" and the outcomes are compared. They were merely observational studies of people going about their normal lives, and as such had little or no power to determine cause and effect. Conceivably, says Boyle, this is a case in which the lines of causation point both ways. In other words, purpose in life may promote better cognitive health, but at the same time, at least to some extent-and Boyle and her colleagues have found evidence for this-good cognitive health helps a person maintain a sense of purpose, which would otherwise fade with the approach of dementia.
However, there is some evidence for specific mechanisms by which well-being might lead to better cognitive health. Perhaps the most obvious involves a reduction in stress. Many studies have determined that stress can adversely affect the brain and cognition, and some have tied stress specifically to the risk of dementia. A long-running Swedish study, for example, found that women who reported experiencing frequent stress during each of three examinations conducted in 1968, 1974, and 1980 were more than twice as likely to develop dementia years later. The study's first author, Lena Johansson of Gothenburg University, notes that among other possible explanations, "Psychological stress increases the activity of the hypothalamic-pituitary-adrenal [system] and thus the levels of stress hormone and corticoid hormones. In previous studies, corticoids have been found to cause structural and functional damage to the brain, and to influence learning and memory processes."
Inflammation also is being looked at as a factor that may connect well being (or its absence) to adverse health effects, including adverse effects on the brain. In a study published in August 2013, a team of collaborating researchers at the University of California at Los Angeles and the University of North Carolina tested 80 people on psychological measures, and also looked at gene expression patterns in their white blood cells. Among these subjects, professing a strong sense of purpose in life was associated with a reduction in a pattern of stress-related gene expression called the Conserved Transcriptional Response to Adversity (CTRA).
The CTRA features an increased expression of central pro-inflammatory genes such as those for NF-kB and tumor necrosis factor (TNF), but also-for reasons that aren't entirely clear-a decreased expression of genes involved in making antibodies. In the study, having a strong sense of purpose in life had an anti-CTRA effect, reducing pro-inflammatory gene activity and increasing antibody-synthesis gene activity.
Eudaimonic vs. hedonic
Intriguingly, this study found that a different type of well-being-"hedonic" well-being, often defined as a simple excess of physical pleasure over pain-was associated with a pro-CTRA effect. Subjects who described themselves as deriving their well-being predominantly from hedonic sources showed an increased activity, on average, of pro-inflammatory genes and reduced activity of antibody synthesis genes. This difference between principally "eudaimonic" and principally "hedonic" subjects was evident despite the fact that the two sets of subjects scored about the same on general measures of mood.
UCLA's Steven W. Cole, the senior author of the study, suspects that eudaimonic well-being is associated with a net resistance to stress-related inflammation mainly because it diversifies the sources of value in a person's life-and, crucially, locates them outside the vulnerable self. "If you derive the bulk of your happiness from consuming, having personal experiences, and other forms of hedonic self-gratification, then when something bad happens to you, it can instantly destroy your entire value pipeline," Cole says. Eudaimonists, by contrast, derive most of their pleasure and meaning from things apart from themselves-political movements, religion and spirituality, team activities, or their families-and are therefore less susceptible to stress when bad things happen on a personal level. "They may feel that the things that they care about most will live on without them," says Cole.
He and his colleagues are still trying to tease apart all the biological effects that follow from stress responses. "But we have at least been able to track down pretty clearly the pathway by which the experience of threat or uncertainty gets converted into the pro inflammatory wing of the CTRA," he says. "We've discovered this by cellular models where we put fight-or-flight hormones on cells and see which genes get turned on and off, and that story lines up pretty well with the observations we can make in human beings and in experimental animal models."
Conceivably, researchers some day could use these data to reproduce the stress resistance of eudaimonists in a pill. "We already can drug those fight-or-flight systems pretty well," Cole says. "We could let people feel threat and distress all they want, but then protect them from the adverse biological consequences of that."
We might even protect ourselves from feeling stress itself-"from being threatened by the slings and arrows of daily life," says Cole. But, he notes, that arguably would change our personalities, not necessarily for the better: "It's all a big cultural exploration at this point about whether that's a good thing to do."