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In the Mind Gut Connection Blog, we have often addressed the relationship between a healthy, Mediterranean-style diet and brain health. We have based many of our recommendations on the consumption of a largely plant-based diet with at least 75% of food coming from a variety of fruits and vegetables, seeds, nuts and olive oil, in addition to an avoidance of ultra-processed foods and sugar. The effects of such a diet on brain health are supported by findings from a number of observational studies (1, 2, 3, 4, 5, 6, 7). In such studies (which make up the majority of published studies on health and diet), researchers compare brain and health outcomes between two usually large groups of individuals, one of which consumes a regular diet, often the Standard American Diet, and the other one consumes a healthy diet. Some evidence links high consumption of green leafy vegetables, nuts, berries, and olive oil with a reduction in the hallmark neuropathologic features of Alzheimer’s disease, such as β-amyloid deposition. As I have discussed in The Gut Immune Connection, even though the proposed underlying mechanisms point to beneficial, anti-inflammatory effects of the microbial metabolites of fiber and polyphenol molecules contained in plant-based foods, a causative role of such a Mediterranean-style diet or of its major ingredients has rarely been demonstrated. Animal models have shown the potential importance of vitamin E and the omega-3 docosahexaenoic acid (DHA) for healthy brain functioning, including protection against lipid peroxidation, neuron loss, β-amyloid deposition, and decline in memory and learning.

A recent study, led by a team of investigators under lead author Dr. Lisa Barnes from Rush University, the Harvard Medical School Department of Nutrition, and the T.H. Chan School of Public Health, published in the prestigious New England Journal of Medicine describes the results of a clinical trials aimed to test the hypothesis that consumption of the MIND Diet compared to a standard American diet led to improved measures of cognition and brain health.

The MIND Diet (The Mediterranean–DASH Intervention for Neurodegenerative Delay), is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, both of which are Mediterranean-style diets with modifications to increase the amounts of foods that have been putatively associated with a decreased risk of dementia. The diet has been introduced by the late Martha Morris (I did a podcast with Dr. Morris several years ago), who also performed several clinical trials with this diet in patients with cognitive decline with positive results.

The investigators performed a two-site, randomized, controlled trial involving healthy older adults without cognitive impairment but with a family history of dementia, a body mass index (BMI) greater than 25, and a suboptimal diet, as determined by a food frequency questionnaire. Even though the study group did not have signs and symptoms of cognitive decline, the increased BMI and a family history of AD are risk factors for the disease. The study compared the cognitive and brain effects of the MIND diet with mild caloric restriction with a control diet with mild caloric restriction. All study participants were followed for 3 years with repeated cognitive testing and received counseling regarding adherence to their assigned diet plus support to promote weight loss. The primary end point was the change from baseline in a global cognition score and four cognitive domain scores, all of which were derived from a 12-test battery. The secondary outcome was the change from baseline in magnetic resonance imaging (MRI)–derived measures of brain characteristics in a smaller number of a non-random sample of participants.

A total of 1929 persons underwent screening, and 604 were enrolled; 301 were assigned to the MIND-diet group and 303 to the control-diet group. The trial was completed by 93.4% of the participants. Surprisingly, from baseline to year 3, small improvements in global cognition scores were observed in both groups, without statistically significant differences. Similarly, the structural grey and white matter changes detected by MRI in a smaller subsample were similar in the two groups. In other words, among cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction.

Previous meta-analyses of diet trials have shown mixed results and generally do not affirm the beneficial effects of diet on cognition that were observed in epidemiologic studies and suggested by preclinical studies. Discrepancies between results from Observational studies or preclinical studies and well-designed intervention trials are common, and there are several reasons that could explain this discrepancy. The presence of bias and confounding in observational studies is one possibility. The notorious unreliability of diet estimates assessed by food frequency questionnaires (FFQs) is another potential confounder. There may be a difference in lifestyle factors other than diet between the groups. In the early studies of the Mediterranean diet, investigators emphasized the importance of such non-dietary lifestyle factors like close and meaningful social interactions and regular daily physical exercise playing an important role in the observed health benefits.

In addition, group differences in the presence of preexisting coexisting medical conditions play a role. The authors also mention the possibility that the participants in the control-diet group probably improved their diet, given evidence of weight loss that was similar in the two groups. And they suggest that it is also plausible that practice effects of repeated cognitive testing could account for improvement in both groups, as has been observed in previous randomized trials.

Based on these study results, should we walk away with the conclusion that dietary interventions have little impact on the development of early cognitive decline and Alzheimer’s disease? Absolutely not! In my opinion, such a reaction would ignore the vast amount of clinical and preclinical research that has been dedicated to reveal the mechanism underlying the development of Alzheimer’s disease. However, given its complex pathophysiology including genetic, environmental, metabolic, immune and gut microbial factors, it does seem unlikely that dietary factors alone are sufficient to explain the development of the disease and the effectiveness of treatments.