Pilot study provides 'blueprint' for evaluating dietary effects on brain health

Researchers from the Johns Hopkins University School of Medicine and the National Institute on Aging at the National Institutes of Health say a study in which 40 older adults with obesity and insulin resistance were randomly assigned to either an intermittent fasting diet or a standard healthy diet approved by the U.S. Department of Agriculture (USDA) offers important clues about the potential benefits of both eating plans for brain health.

This paper Published In the journal Cell metabolism.

Insulin resistance is a hallmark of type 2 diabetes and is common in obese people. Research suggests that people with insulin resistance are at higher risk for Alzheimer's disease and other cognitive disorders. Therefore, various weight loss therapies are widely considered as a way to reduce the risk of these metabolic and brain disorders.

Previous studies conducted by Johns Hopkins University in animal models of diabetes and Alzheimer's disease have shown that intermittent fasting can improve cognitive function and insulin sensitivity. The new study tested the effects of intermittent fasting on women and men at risk for cognitive impairment. The authors write that the study provides a “blueprint” for assessing the diet's impact using a wide range of biomarkers, including analysis of extracellular vesicles — tiny chunks of material released by neurons, a type of brain cell that transmits messages. Such neuron-derived extracellular vesicles are released into circulating blood and were collected over eight weeks from participants in the new study, each of whom followed one of two diets.

According to Dr. Mark Mattson, an adjunct professor of neuroscience at the Johns Hopkins University School of Medicine and former director of the Neuroscience Laboratory at the National Institute on Aging in Baltimore, the results showed that both types of diets had benefits in terms of reducing insulin resistance and improving cognition, and that improvements in memory and executive function were seen with both diets, but the effects were more pronounced with the intermittent fasting diet.

“Other scientists may want to incorporate the[brain]markers[we used]into larger studies of diet and brain health,” Mattson said.

Because people with obesity and insulin resistance may be at higher risk for cognitive impairment and Alzheimer's disease than those with normal metabolism and BMI, Dimitrios Kapogiannis, MD, PhD, chief of the Division of Human Neuroscience at the National Institute on Aging and adjunct associate professor of neurology at the Johns Hopkins University School of Medicine, developed a method to isolate neuron-derived extracellular vesicles from blood. His lab has found molecular evidence of insulin resistance in extracellular vesicles shed from neurons in patients with diabetes and Alzheimer's disease, and because blood samples are relatively easy to obtain, they seemed like a good candidate for widespread use.

To test the effects of the two diets on biomarkers of brain function, participants in the new study were recruited from June 2015 to December 2022 and underwent four in-person assessments at a facility run by the National Institute on Aging at MedStar Harbor Hospital in Baltimore.

Forty of the participants completed the eight-week study. Twenty also followed an intermittent fasting diet, limiting calories to one-quarter of the daily recommended intake, for two consecutive days per week, and followed the USDA Healthy Living Diet (fruits, vegetables, whole grains, lean protein, low-fat dairy, and limiting added sugars, saturated fats, and sodium) for the remaining five days of the week. The USDA Healthy Living Diet was assigned to the other 20 study participants for each day of the week.

The average age of participants in both groups was 63 years old. There were 25 white, 14 black, and one Hispanic. There were 24 men and 16 women. All were obese and insulin resistant.

The researchers found that both diets had similarly positive effects on reducing insulin resistance markers in extracellular vesicles, improving BrainAGE (a measure of the brain's biological age using structural MRI data), and reducing glucose concentrations in the brain, which is a corollary of increased glucose usage.

Both diets improved the usual measures of metabolic health, including weight, BMI, waist circumference, blood lipids such as cholesterol, and insulin resistance.

Executive function and memory (a set of mental skills that help you plan and achieve your goals) were about 20% better in the intermittent fasting group than in the healthy eater group.

Some study participants reported mild side effects, including constipation, loose stools, and occasional headaches.

The researchers also found elevated levels of neurofilament proteins (structural proteins in neurons) in both diet groups, but mainly in the intermittent fasting group. What this means in terms of brain health is unclear.

“This is an indicator that we will continue to evaluate in future studies,” Mattson said. “Neurons release many proteins, and the idea is that intermittent fasting may be causing some kind of neuroplasticity (changes in structure) in neurons, which causes the release of neurofilament proteins.”

Johns Hopkins University researchers caution that intermittent fasting can be harmful for some people, such as those with type 1 diabetes or eating disorders, so people interested in trying it should plan carefully with their health care provider.