Cover Story

With a nation of baby boomers marching toward old age, the medical community has been poised for a wave of new dementia cases. That hasn't materialized. A new study by Kenneth Langa, MD, PhD, at the University of Michigan and colleagues found that the prevalence of dementia in the United States actually dropped in recent years, from 11.6 percent of people over age 65 in 2000 to 8.8 percent in 2012 (JAMA Internal Medicine, 2017).

The study was an observational one, so the scientists can't say for sure what drove that decline. Factors such as better control of high blood pressure and greater educational attainment could help to explain the drop, Langa and his colleagues say.

In recent years, researchers have made strides in understanding how those and other factors might help prevent dementia. As it turns out, cognitive and psychological factors can go a long way toward protecting the brain. Now the task will be to translate that research into interventions that can delay or prevent the onset of dementia.

"This is a disease whose primary manifestations are psychological in nature, and psychologists will have a big role to play as we try to develop behavioral interventions," says Robert S. Wilson, PhD, a neuropsychologist at the Rush University Alzheimer's Disease Center.

A long time coming

Roughly 5 million people in the United States are estimated to be living with dementia, marked by such cognitive changes as memory loss, impaired reasoning and personality changes. Alzheimer's disease is the most common cause, accounting for 60 percent to 80 percent of dementia diagnoses, according to the Alzheimer's Association. The disease is attributed to two types of abnormal protein clusters in the brain: amyloid plaques, which build up in the spaces between nerve cells, and neurofibrillary tangles of the protein tau, which build up inside cells.

Other forms of dementia can be related to changes in the brain such as Lewy bodies (abnormal deposits of the protein alpha-synuclein in the brain), vascular problems that reduce blood flow to the brain or microinfarcts (microscopic strokes).

Once visible only at autopsy, the plaques and tangles of Alzheimer's disease can now be identified in the brains of living people. Those advances are giving researchers a new understanding of the brain changes that underlie dementia. But what they're finding is a complicated picture, Wilson says. Plaques and tangles, for instance, often co-appear with other abnormalities, such as vascular problems or microinfarcts. "We now understand that dementia in old age is usually caused by a mixture of pathologies," he says.

Some of those pathologies, such as Lewy bodies, are still impossible to detect in living brains. What's more, many people have amyloid buildup but no outward symptoms of dementia. That makes it difficult to understand what's going on in the brain of a person with dementia symptoms. "We're pretty good at recognizing dementia, but we're not so good at tracking down what it is due to in an individual case," Wilson says.

Whatever is happening in any given brain, though, it clearly takes its time. Brain changes gradually accumulate for a decade or more before any symptoms appear, Wilson explains. And even then, it can take years for the first subtle signs of mild cognitive impairment to progress to full-blown dementia.

"The symptomatic phase is the beginning of very subtle changes in cognitive function, and dementia is really the end stage of a very long, drawn-out process that goes on for decades," he says. "So, it makes sense to try to treat it before there's irreversible brain damage."

Many in the research community are turning fresh attention toward preventing or delaying dementia — especially after several recent drug trials failed to show improvements in people who already have symptoms, says Reisa Sperling, MD, director of the Center for Alzheimer's Research and Treatment at Brigham and Women's Hospital in Boston. "Unfortunately, the past two years have seen a lot of disappointing results. We're left wondering if we're doing too little, or doing it too late. And I think we are starting too late."

So she's now heading a large new trial called the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study, which is testing a drug that she hopes might prevent healthy adults with normal memory from developing Alzheimer's disease. She and her colleagues are using neuroimaging to identify participants who have amyloid plaques in their brains yet do not show signs of impairment.

Being able to identify brain changes associated with dementia in living patients has revolutionized the way researchers recruit participants for such studies, Sperling says. Psychology's role remains essential to that development, she adds, because neuropsychological tests are still critical for identifying early signs of cognitive impairment. "The bottom line is not what your biomarkers look like," she says. "It's whether your memory worsens."

Healthy body, healthy brain

While drug treatments might hold promise for preventing dementia, medications aren't the only possibility. Researchers are also exploring cognitive and lifestyle factors that can shield the brain from dementia.

Many studies have looked at dietary factors, for instance. A new observational study by Matthew P. Pase, PhD, at Boston University and colleagues found that regularly drinking artificially sweetened soda increases the risk of stroke and dementia (Stroke, 2017). But so far, there are no dietary interventions that have been shown to effectively prevent dementia in randomized trials, Sperling says.

Exercise to ward off dementiaExercise, though, has more robust evidence of a protective effect, as J. Eric Ahlskog, PhD, MD, and colleagues describe in a 2011 review (Mayo Clinic Proceedings, 2011). Multiple studies have shown that regular physical activity in midlife reduces the risk of dementia in later life, they report. And among patients with dementia or mild cognitive impairment, those who followed exercise regimens for six to 12 months in randomized controlled trials had better cognitive scores than more sedentary control participants.

There's also evidence that exercise physically changes the brain. In one example, Kirk I. Erickson, PhD, Arthur F. Kramer, PhD, and colleagues found older adults who engaged in a year of moderate aerobic exercise three days a week had an increase in the volume of the hippocampus compared with controls, who saw a small loss of hippocampus volume over the same period. And that brain-size difference was linked to better memory in the exercise group (PNAS, 2011).

Exercise is also known to increase levels of brain-derived neurotrophic factor, a protein necessary for maintaining healthy neurons. On top of that, physical activity is important for maintaining vascular health — and vascular disease is itself a risk factor for dementia.

Researchers have long known that vascular diseases such as high blood pressure can damage the brain's blood vessels and cause vascular dementia, says Margaret Gatz, PhD, a professor of psychology, gerontology and preventive medicine at the University of Southern California. More recently, it's become clear that vascular diseases, including midlife diabetes, increase the risk of Alzheimer's disease as well. But it's not yet entirely clear how they do so, Gatz says.

Researchers are still exploring the mechanisms that link exercise and physical health to healthier brains. Such factors help maintain brain integrity, and there are some data to hint that they might even prevent plaques, tangles or other brain pathologies from forming in the first place, says Yaakov Stern, PhD, a neuropsychologist at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University.

Factors that maintain the brain and prevent brain pathology are akin to improving the brain's underlying hardware, Stern says. Other factors, meanwhile, are thought to allow the brain to keep functioning normally even as detrimental changes accumulate — much like software that allows a computer to keep running despite faulty hardware.

"The idea is that some people can better cope with the pathology and the brain changes as they occur," Stern says.

This capacity, known as cognitive reserve, helps explain an interesting paradox: A significant number of people die with Alzheimer's pathology in the brain, but no outward evidence of dementia.

According to Wilson's studies, about a third of people who die with no apparent cognitive impairment have Alzheimer's pathology in their brains—and not just a few plaques or tangles, but enough to meet the current pathological criteria for the disease. "What was it that allowed these people to tolerate the disease and go on functioning pretty well? If we can learn that, we could make a dent in the impact of these diseases," he says.

Building cognitive reserve

Over the past decade or two, researchers have amassed a convincing pile of evidence that might best be summed up as "use it or lose it." Just as working out keeps the body strong, exercising your brain with mentally stimulating activities such as education, challenging careers and plentiful leisure activities appears to slow the march of cognitive decline.

People who participated in frequent leisure activities such as knitting, music, reading or volunteer work were less likely to develop dementia.Stern has explored the cognitive reserve idea for years and summarized many of his findings in a recent review (Lancet Neurology, 2012). He and his colleagues have found, for instance, that people who participated in frequent leisure activities such as knitting, music, reading or volunteer work were less likely to develop dementia than those who rarely engaged in such hobbies. Dementia was less likely in people who held skilled or professional jobs, compared with those with lower-skilled careers. And people with more than eight years of formal education were less likely to develop dementia than those who had fewer than eight years of education.

Gatz has also explored factors that might protect against dementia in a long-term study following pairs of Swedish twins in which only one sibling has dementia. She and former student Michael Crowe, PhD, and colleagues found that people who participate in more leisure activities have a lower risk of cognitive impairment (Journals of Gerontology Series B, 2003). Interestingly, though, intellectually demanding leisure activities were protective only for women, they found.

Gatz and her former student Ross Andel, PhD, and colleagues also explored the link between dementia and careers. They found that people who had engaged in more complex work dealing with other people had lower rates of Alzheimer's disease (Journals of Gerontology Series B, 2005). "It turns out the social factor is probably the most protective aspect of one's occupation," Gatz says. "It's not about standing around chatting at the water cooler, but managing others. Using complex problem-solving for cooperative efforts seems to be protective."

But while cognitive reserve seems to be important, it can't always hold off dementia indefinitely. Stern has found that once people with greater levels of educational and occupational attainment start to exhibit symptoms of Alzheimer's disease, they have more rapid cognitive decline and die sooner than those with less cognitive reserve. In other words, cognitive reserve seems to allow people to maintain function until the brain changes are so severe that they overwhelm the system.

Autopsy studies also support the theory that cognitive reserve can make the brain more resilient to disease. Wilson and colleagues found people who had engaged in cognitively stimulating activities (such as reading, visiting libraries and writing letters) across their life spans had slower late-life cognitive decline. When the researchers examined those participants' brains after their deaths, however, they found they still had evidence of plaques, tangles and Lewy bodies in their brains (Neurology, 2013).

Seeking interventions

Because dementia is a disease that usually occurs at the end of life, people with a beefed-up cognitive reserve have a better chance of dying of other causes before their thinking becomes muddled and their memories slip away. "We'll probably never completely prevent dementia, but if we could delay it a little bit, it could have a huge public health impact," Wilson says.

So far, most of the evidence suggests that cognitive reserve is something that builds over a lifetime. That means you probably can't take up writing poetry or playing the clarinet at age 80 and expect it will fill your cognitive tank. "When we say lifestyle factors might affect your risk of dementia, we're talking about chronic behavior patterns over many years," Wilson says.

Nevertheless, researchers haven't given up on the idea of developing late-life interventions to slow cognitive decline. "We've had some very promising results," says George Rebok, PhD, a professor in the department of mental health at the Johns Hopkins Bloomberg School of Public Health who studies cognitive decline. He has been involved with the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial, a multisite cognitive intervention to slow cognitive decline and functional loss in older adults.

That trial recruited cognitively healthy older adults and provided 10 training sessions, each 60 to 75 minutes long, which targeted one of three types of cognitive ability: memory, reasoning and problem solving, or speed of processing. As expected, each group showed improvements on the specific skill they were trained on. More important, Rebok and his colleagues found that those improvements translated to lasting improvements in everyday activities, such as managing finances or planning meals (Journal of the American Geriatrics Society, 2014).

"All three of the intervention groups reported experiencing less difficulty carrying out activities of daily living, and the effects were significant up to 10 years after the intervention," he says.

That trial focused on normal age-related decline, not dementia. Still, it suggests that cognitive training later in life could help shore up cognitive reserve and perhaps even slow the onset of dementia.

Overall, though, brain-training interventions that aim to slow cognitive decline have had mixed results. Those that have been more successful tend to target multiple components besides cognitive training, Rebok says. One encouraging finding came from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. Older adults at high risk of cognitive decline were randomly assigned to receive general health information or a two-year intervention addressing diet, exercise, cognitive training and vascular risk monitoring. Those who participated in the intervention group showed significantly improved cognitive function compared with controls (The Lancet, 2015).

It's a promising finding, Rebok says, though a lot more work is needed to determine how to design interventions that target many cognitive and lifestyle factors at once. After all, interventions won't be effective unless people actually use them. "There's a lot more we need to learn about putting these interventions together so we don't overburden participants," he says.

And leading people to change, adds Gatz, might be one of the hardest pieces in the dementia prevention puzzle. "If I were writing an advice column, I'd tell people to do all the recommended midlife controls for diabetes, blood pressure, cholesterol and develop a really good exercise habit. But they already know that," she says. "We need more research on how to get people to do what they know they should do."

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Further resources

Memory & Aging
APA Office on Aging

APA Guidelines for the Evaluation of Dementia and Age-Related Cognitive Change

Healthy Cognitive Aging and Dementia Prevention
Smith, G.E.
American Psychologist, 2016