For the past 3 years, about 6000 middle-aged and elderly Australians have pumped iron, loaded up on greens and whole grains, strived to quell stress, and challenged their wits with computer exercises, all in an effort to preserve their cognition. They’re part of a clinical trial called Maintain Your Brain, one of about 30 current or planned studies that eschew pharmaceutical interventions and test whether altering multiple aspects of participants’ lives improves brain health. Such multidomain studies may finally reveal whether modifying diet, exercise, and other factors can slow cognitive decline as people age—or even prevent dementia.
“There’s a lot of hope for multidomain trials,” says psychologist Kaarin Anstey of the University of New South Wales, Sydney, one of the principal investigators of the Maintain Your Brain trial, which will finish by the end of this year.
Although people can’t escape some mental decline as they get older, lifestyle exerts a powerful influence over the risk of developing dementia—the type of severe cognitive impairment seen in conditions such as Alzheimer’s disease. Last year, an international committee of scientists and psychiatrists known as the Lancet Commission on dementia prevention, intervention, and care estimated that so-called modifiable factors account for 40% of dementia risk. Their report highlighted a dozen factors, including many familiar villains—diabetes, high blood pressure, smoking, obesity, and lack of exercise.
Researchers are still probing exactly how these risk factors steal people’s faculties, but they’ve identified some likely mechanisms. Lack of physical activity may impair cognition, for instance, because exercise stimulates formation of new neurons and soothes brain inflammation.
For decades scientists concentrated on developing drugs to treat Alzheimer’s disease, but after several candidates recently failed in clinical trials, “the climate has really shifted to focus on … prevention,” says neuropsychiatrist and epidemiologist Kristine Yaffe of the University of California, San Francisco. Some researchers urge governments to step up dementia prevention with measures such as public health campaigns that encourage salutary habits. “We have knowledge about some of the actions to take for society to make a difference,” says psychiatrist Gill Livingston of University College London, who heads the Lancet Commission. “The time is now.”
The combined effect of lifestyle factors is strong, but researchers lack conclusive evidence that modifying any of them spares the brain. “A gazillion observational studies” point to factors that influence cognitive aging, Yaffe says. “Can we say, ‘Do X, Y, and Z and that will prevent Alzheimer’s disease’? I don’t think so.”
Large, randomized, controlled trials would provide the strongest support for particular interventions. But these costly studies are rare. Multiyear trials, which have the best shot at detecting an impact on a slow-developing condition like dementia, are even rarer.
The only study to show that any lifestyle intervention cuts dementia risk was the Advanced Cognitive Training for Independent and Vital Elderly trial, launched in the late 1990s. A group of nearly 700 elderly people in the study underwent 6 weeks of cognitive training to improve their thinking speed. Ten years later, they had a 6% lower incidence of dementia than participants who received no training. But the benefits of “brain training” remain unsettled, and many commercially available games and apps lack rigorous evidence to support their claims.
Scientists are eager to nail down the value of other interventions. Observational studies suggest the Mediterranean diet, which is heavy on olive oil, fish, and whole grains but light on red meat and sugars, improves some aspects of cognition. But no large, randomized, controlled trial has tested the preventive effects of switching to the diet—or compared it with other promising regimens such as dietary approaches to stop hypertension (DASH), designed to reduce blood pressure. A 3-year study wrapping up later this year will evaluate the Mediterranean-DASH intervention for neurodegenerative delay diet, which merges the Mediterranean and DASH diets, in 600 people over age 60 who are at high risk for developing dementia. That could provide “the first evidence of whether changing diet prevents cognitive decline in older adults,” says cognitive neuropsychologist Lisa Barnes of Rush University, principal investigator of the $14 million, NIH-funded study.
However, most randomized trials that have focused on only one aspect of lifestyle have come up empty. Many researchers agree that multidomain trials like Maintain Your Brain offer a better chance of finding meaningful effects. Dementia results from multiple causes, the argument goes, so preventing it will require a combination of interventions.
A Finnish trial launched in 2009 was the pioneer of the genre. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included 1260 people in their 60s and 70s who were susceptible to dementia because of risk factors such as hypertension. Half of them took part in an intensive program to improve their diet, heart health, mental acuity, and exercise habits. The control group received health advice from nurses but no help implementing it.
The finding that people in the intensive program improved their cognitive test scores over the 2-year study period electrified a major Alzheimer’s conference in 2014, says Heather Snyder, vice president for medical and scientific relations at the nonprofit Alzheimer’s Association. “It was the first study to demonstrate on that scale and scope that these interventions in synergy could affect cognition.”
Two similar studies, conducted in the Netherlands and France, also suggested a cognitive benefit in a subset of people with high dementia risk. No one knows how long the effects persist or whether the interventions prevent dementia, but ongoing follow-up of FINGER participants might provide some answers.
Now, scientists in other countries are setting up trials tailored to the diets and habits of their populations. One of Maintain Your Brain’s goals is to determine whether multidomain interventions can be delivered remotely. Participants log into the trial’s website to obtain coaching, access materials such as cooking demonstrations, and record their progress.
The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk, scheduled to finish in 2024, aims to reproduce the results of the FINGER trial in the more racially and ethnically diverse U.S. population. It will test whether subjects do better when they are assigned a specific plan or when they have freedom to customize their own. “If we can create a sustainable program that’s accessible for everyone … that would be a huge success,” says cognitive neuroscientist Laura Baker of Wake Forest School of Medicine, who heads the trial.
Whether lifestyle changes can stall dementia or cognitive decline remains unproved for now, but Baker anticipates a mountain of new evidence. “In the next 10 years, we will see if lifestyle works.”
sciencemag.org, 27 May 2021