Another difficulty is that these surveys often don’t account for variables that could be really important, like how the food was prepared and where it came from. Was the fish grilled? Fried? Slathered in butter? “Those things can matter,” says dementia researcher Nathaniel Chin of the University of Wisconsin–Madison.

Plus there are the things researchers can’t control. For example, how does the food interact with an individual’s medications and microbiome? “We know all of those factors have an interplay,” Chin says.

The few clinical trials looking at dementia and diet seem to measure different things, so it’s hard to make comparisons. In 2018, Radd-Vagenas and her colleagues looked at all the trials that had studied the impact of the Mediterranean diet on cognition. There were five at the time. “What struck me even then was how variable the interventions were,” she says. “Some of the studies didn’t even mention olive oil in their intervention. Now, how can you run a Mediterranean diet study and not mention olive oil?”

Another tricky aspect is recruitment. The kind of people who sign up for clinical trials tend to be more educated, more motivated and have healthier lifestyles. That can make differences between the intervention group and the control group difficult to spot. And if the study shows an effect, whether it will apply to the broader, more diverse population comes into question. To sum up, these studies are difficult to design, difficult to conduct and often difficult to interpret.

Kaeberlein studies aging, not dementia specifically, but he follows the research closely and acknowledges that the lack of clear answers can be frustrating. “I get the feeling of wanting to throw up your hands,” he says. But he points out that there may not be a single answer. Many diets can help people maintain a healthy weight and avoid diabetes, and thus reduce the risk of dementia. Beyond that obvious fact, he says, “it’s hard to get definitive answers.”

A better way

In July 2021, Yassine gathered with more than 30 other dementia and nutrition experts for a virtual symposium to discuss the myriad challenges and map out a path forward. The speakers noted several changes that might improve the research.

One idea is to focus on populations at high risk. For example, one clinical trial is looking at the impact of low- and high-fat diets on short-term changes in the brain in people who carry the genetic variant APOE4, a risk factor for Alzheimer’s. One small study suggested that a high-fat Western diet actually improved cognition in some individuals. Researchers hope to get clarity on that surprising result.

Another possible fix is redefining how researchers measure success. Hypertension and diabetes are both well-known risk factors for dementia. So rather than running a clinical trial that looks at whether a particular diet can affect dementia, researchers could look at the impact of diet on one of these risk factors. Plenty of studies have assessed the impact of diet on hypertension and diabetes, but Yassine knows of none launched with dementia prevention as the ultimate goal.

Yassine envisions a study that recruits participants at risk of developing dementia because of genetics or cardiovascular disease and then looks at intermediate outcomes. “For example, a high-salt diet can be associated with hypertension, and hypertension can be associated with dementia,” he says. If the study shows that the diet lowers hypertension, “we achieved our aim.” Then the study could enter a legacy period during which researchers track these individuals for another decade to determine whether the intervention influences cognition and dementia.

One way to amplify the signal in a clinical trial is to combine diet with other interventions likely to reduce the risk of dementia. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, or FINGER, trial, which began in 2009, did just that. Researchers enrolled more than 1,200 individuals ages 60 to 77 who were at an elevated risk of developing dementia and had average or slightly impaired performance on cognition tests. Half received nutritional guidance, worked out at a gym, engaged in online brain-training games and had routine visits with a nurse to talk about managing dementia risk factors like high blood pressure and diabetes. The other half received only general health advice.

After two years, the control group had a 25 percent greater cognitive decline than the intervention group. It was the first trial, reported in the Lancet in 2015, to show that targeting multiple risk factors could slow the pace of cognitive decline.

Now researchers are testing this approach in more than 30 countries. Christy Tangney, a nutrition researcher at Rush University in Chicago, is one of the investigators on the U.S. arm of the study, enrolling 2,000 people ages 60 to 79 who have at least one dementia risk factor. The study is called POINTER, or U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk. The COVID-19 pandemic has delayed the research — organizers had to pause the trial briefly — but Tangney expects to have results in the next few years.

This kind of multi-intervention study makes sense, Chin says. “One of the reasons why things are so slow in our field is we’re trying to address a heterogeneous disease with one intervention at a time. And that’s just not going to work.” A trial that tests multiple interventions “allows for people to not be perfect,” he adds. Maybe they can’t follow the diet exactly, but they can stick to the workout program, which might have an effect on its own. The drawback in these kinds of studies, however, is that it’s impossible to tease out the contribution of each individual intervention.

Embracing complexity 

To untangle the role of diet in dementia, researchers are designing trials that intervene earlier in life and last longer. Some studies combine multiple interventions, like diet, exercise and brain training, as well as measure a wider range of outcomes.

Dementia and diet studies are due a makeover

Preemptive guidelines

Two major reports came out in recent years addressing dementia prevention. The first, from the World Health Organization in 2019, recommends a healthy, balanced diet for all adults, and notes that the Mediterranean diet may help people who have normal to mildly impaired cognition.

The 2020 Lancet Commission report, however, does not include diet in its list of modifiable risk factors, at least not yet. “Nutrition and dietary components are challenging to research with controversies still raging around the role of many micronutrients and health outcomes in dementia,” the report notes. The authors point out that a Mediterranean or the similar Scandinavian diet might help prevent cognitive decline in people with intact cognition, but “how long the exposure has to be or during which ages is unclear.” Neither report recommends any supplements.

Plenty of people are waiting for some kind of advice to follow. Improving how these studies are done might enable scientists to finally sort out what kinds of diets can help hold back the heartbreaking damage that comes with Alzheimer’s disease. For some people, that knowledge might be enough to create change.

“Inevitably, if you’ve had Alzheimer’s in your family, you want to know, ‘What can I do today to potentially reduce my risk?’ ” says molecular biologist Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association.

But changing long-term dietary habits can be hard. The foods we eat aren’t just fuel; our diets represent culture and comfort and more. “Food means so much to us,” Chin says.

“Even if you found the perfect diet,” he adds, “how do you get people to agree to and actually change their habits to follow that diet?” The MIND diet, for example, suggests people eat less than one serving of cheese a week. In Wisconsin, where Chin is based, that’s a nonstarter, he says.

But it’s not just about changing individual behaviors. Radd-Vagenas and other researchers hope that if they can show the brain benefits of some of these diets in rigorous studies, policy changes might follow. For example, research shows that lifestyle changes can have a big impact on type 2 diabetes. As a result, many insurance providers now pay for coaching programs that help participants maintain healthy diet and exercise habits.

“You need to establish policies. You need to change cities, change urban design. You need to do a lot of things to enable healthier choices to become easier choices,” Radd-Vagenas says. But that takes meatier data than exist now.

Tags:shifting,How,