Greater adherence to the MIND diet was linked to less brain tissue loss over time, particularly in grey matter, which plays an important role in memory, learning, decision making, and information processing. It was also associated with less enlargement of the brain’s ventricles, fluid filled spaces that tend to grow as brain tissue shrinks.

What Is the MIND Diet?

The Mediterranean-Dietary Approaches to Stop Hypertension Diet Intervention for Neurodegenerative Delay diet, or MIND for short, has previously been associated with better cognitive health, according to the researchers.

The eating pattern emphasizes green leafy vegetables; other vegetables; berries; nuts; whole grains; fish; beans; olive oil; and poultry, along with moderate wine consumption. It also recommends limiting butter/margarine, cheese, red meat, pastries/sweets, and fried fast foods.

Although previous research has connected the MIND diet with cognitive benefits, its relationship with age related changes in brain structure has remained less clear. Those structural changes are also relevant to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases.

Researchers Tracked Brain Changes for Years

To investigate, researchers studied 1647 middle aged and older adults (average age 60 at the start of the study) from the Framingham Heart Study Offspring cohort (FOS).

Participants underwent regular health evaluations every 4-8 years. Starting in 1999, they also received MRI brain scans every 2-6 years.

Diet was assessed through at least 1 food frequency questionnaire (FFQ) completed during check ups between 1991-5, 1995-8, and/or 1998-2001. Each participant also had at least 2 brain MRI scan assessments between 1999 and 2019 and showed no evidence of stroke or dementia at the time of their first MRI scan.

The average MIND diet score was just under 7 out of a possible 15, with 15 representing the strongest adherence.

People in the highest third for MIND diet adherence were more likely to be women and college educated. They were also less likely to smoke or have obesity.

They were also less likely to have conditions that can affect brain health, including type 2 diabetes, high blood pressure, and cardiovascular disease.

Higher MIND Scores Linked to Slower Grey Matter Loss

Over an average follow up period of 12 years, MRI scans showed the expected age related changes across the group. These included decreases in total brain, grey matter, white matter, and hippocampal volumes.

At the same time, cerebrospinal fluid and ventricular volumes increased, as did white matter hyperintensities, which appear as bright spots on MRI scans and can indicate tissue damage.

However, people with higher MIND diet scores experienced slower loss of grey matter.

Each 3 point increase in MIND diet score was associated with slower grey matter loss of (0.279 cm³/year). According to the researchers, that corresponded to 20% less age related decline and the equivalent of 2.5 years of delayed brain aging.

A similar pattern appeared in ventricular enlargement. Each 3-point rise in MIND diet score was associated with slower expansion of total ventricular volume by −0.071 cm³/year, equivalent to 8% less tissue loss and about 1 year of delayed brain aging.

Berries and Poultry Stand Out

Some foods appeared to contribute more strongly to the favorable associations.

Higher berry intake was linked to slower increases in ventricular volume. Poultry was also associated with slower ventricular enlargement, along with a slower decline in grey matter.

In contrast, higher consumption of sweets was associated with faster ventricular enlargement and greater hippocampal atrophy. Fried fast foods were also linked to a larger decline in hippocampal volume.

“MIND-recommended foods rich in antioxidants, such as berries, and high-quality protein sources like poultry may reduce oxidative stress and mitigate neuronal damage,” suggest the researchers. “Conversely, fried fast foods, often high in unhealthy fats, trans fats, and advanced glycation end-products, may contribute to inflammation and vascular damage,” they add.

Some Findings Were Unexpected

Not every food produced the expected pattern.

Higher whole grain intake was associated with several unfavorable structural changes, including faster losses of grey matter and hippocampal volume, as well as faster ventricular enlargement.

Cheese showed the opposite pattern. Greater cheese intake was associated with slower declines in grey matter and hippocampal volume, less ventricular enlargement, and fewer white matter hyperintensities.

Benefits Appeared Stronger in Older Adults

The overall associations remained consistent across several additional analyses and were stronger among older participants.

The researchers say this may suggest that the MIND diet could be especially relevant for people at greater risk of faster brain aging or those who show more variation in the pace of brain atrophy.

Stronger associations were also seen among participants who were more physically active and among those who were not overweight or obese.

That pattern raises the possibility that combining a brain healthy diet with other healthy lifestyle habits could help reduce the risk of neurodegenerative disease, the researchers say.

The Study Cannot Prove Cause and Effect

The findings come from an observational study, so they cannot establish that the MIND diet directly caused the slower brain changes.

The researchers also note that food frequency questionnaires rely on participants accurately remembering what they ate, which can introduce recall bias.

They were also unable to rule out mild cognitive impairment at the time of the first MRI scan, changes in diet over time, or the influence of genetic risk factors.

Because the participants were predominantly White, the findings may not apply equally to people from other ethnic backgrounds.

Still, the researchers conclude: “These findings reinforce the potential of the MIND diet as a brain-healthy dietary pattern and support its role in strategies aimed at slowing neurodegeneration in aging populations.”

Published Sept. 23 in JAMA Psychiatry, the study was funded by the National Institutes of Health. Researchers believe it is the first study to compare depression symptoms in the same participants before and after they moved from their usual ultra-processed diet to healthier foods.

The pilot study included only 20 people, but senior author Andrew Krystal, MD, Ray and Dagmar Dolby Distinguished Professor in UCSF’s departments of Psychiatry and Behavioral Sciences and Neurology, said it “successfully established the viability of carrying out this research in a larger-scale trial.”

Depression Symptoms Improved After a Major Diet Shift

Participants cut their intake of ultra-processed foods by more than 85%. After doing so, they showed moderate to large improvements across three different measures of depression. Anxiety scores also improved modestly.

Ultra-processed foods include products such as packaged snacks, fast food, sugary drinks, and other industrially manufactured foods. These products may contain ingredients including preservatives, artificial coloring, flavor enhancers, and emulsifiers.

“Reducing the amount of ultra-processed food in our diet can be challenging, because it’s highly palatable, cheap, and convenient,” said corresponding author Nyasha Chagwedera, MD, PhD, assistant professor in the UCSF Department of Psychiatry and Behavioral Sciences. “Ultra-processed food triggers dopamine, the pleasure hormone, which promotes craving. Food companies work with scientists to find just the right amount of sugar, salt, and fat that make you want to eat more and more.”

Testing the Gut-Brain Connection

The participants had an average age of 44, and 70% were female. Along with depression, 14 participants also had anxiety. Everyone in the study had a high BMI and at least one metabolic disorder — such as hypertension, diabetes, or elevated LDL cholesterol.

Researchers divided the participants into two groups. One group stayed on its usual diet for four weeks, while the other switched to a diet low in ultra-processed foods. Participants selected and bought their own food with guidance from the research team. After four weeks, the groups switched diets.

Chagwedera, who founded the UCSF Metabolic and Mental Health Program, said one possible explanation for the connection between ultra-processed food and depression involves what she described as a “leaky, out-of-balance gut.” According to this idea, ultra-processed foods may damage the protective lining of the gut.

“This gut damage can create low-grade, chronic inflammation throughout the body that either directly causes depression or makes people more vulnerable to it.”

“In other words, junky processing may harm your gut in ways that ripple up to your brain.”

Larger Depression Trial Planned

Because the study was small, the findings are still preliminary. The researchers now plan to investigate the effect in a larger group, with enrollment for phase 2 expected to begin in 2028.

Authors: Additional UCSF authors include Eliana Kim, MD, Dorothy T. Chiu, PhD, Chengshi Jin, PhD, Catherine Lee PhD. Other authors are Susannah Tye, PhD, of the University of Queensland, Australia, Mayo Clinic, and Emory University.

Funding: National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 TR001872; NHLBI grant R38AG070171, NIMH grant R38AG070171, and the UCSF Weill Institute of Neurosciences.

Alzheimer’s disease gradually damages memory, thinking, and behavior and affects more than 7 million older adults in the United States. Researchers have known for years that blood vessels in the brain deteriorate as Alzheimer’s progresses, especially in people who carry APOE4. What has been less clear is why this happens and whether the vascular damage contributes directly to the disease. Because of that uncertainty, damage to the brain’s circulation has often been treated as a consequence of Alzheimer’s rather than as a process that could help drive it.

Mapping How APOE4 Damages Brain Blood Vessels

For the Cell study published on September 24, Mount Sinai scientists combined existing datasets to build a single cell transcriptomic atlas of blood vessels in the human brain. The resulting map showed patterns of gene activity across the different cells that create and support the brain’s vascular system, giving researchers a detailed way to examine how APOE4 contributes to vascular degeneration.

The team found that APOE4 altered the behavior of pericytes. These cells normally help stabilize small blood vessels and support the blood brain barrier. In the presence of APOE4, however, the pericytes changed into myofibroblast-like cells that produce scar tissue.

That transformation promoted vascular fibrosis and increased the buildup of amyloid around blood vessels. These changes could interfere with blood flow and create conditions that encourage neurodegeneration.

The researchers also found evidence that this process could be reversed. Blocking TGF-β signaling, which plays a role in communication between cells and in tissue remodeling, restored pericyte coverage while reducing fibrosis and amyloid around blood vessels. The researchers reproduced the result in aged APOE4 mice, showing that the vascular degeneration associated with APOE4 can be therapeutically reversed.

“Damage to the brain’s blood vessels is not simply a late consequence of Alzheimer’s disease; it is a biologically active process caused by APOE4 that may be reversible,” said corresponding author Joel W. Blanchard, PhD, Associate Professor of Neuroscience, and Stem Cell Biology and Regenerative Medicine, at the Icahn School of Medicine at Mount Sinai. “These findings reveal new therapeutic targets for preserving vascular function and limiting amyloid accumulation.”

“We show that APOE4 converts blood-vessel support cells into scar-producing cells, causing amyloid or abnormal protein buildup to accumulate around the brain’s vessels. Through our experiments, we were able to block this protein buildup process, revealing possible new therapeutic treatment options and strategies for protecting the brain’s circulation in people at high genetic risk for Alzheimer’s disease,” said first author Braxton R. Schuldt, MD/PhD candidate in Neuroscience and researcher in the Blanchard Laboratory at the Icahn School of Medicine at Mount Sinai.

Human miBrains Reveal Disease Mechanisms

A major part of the research relied on miBrains, three dimensional human brain tissue developed by the Mount Sinai team from induced pluripotent stem cells. The model reproduces important features of human brain tissue, including its network of blood vessels.

The Blanchard laboratory combined findings from miBrains with preclinical models, postmortem human brain tissue, and transcriptomic data. Each approach helped confirm and expand on observations made with the others.

By bringing these systems together, the scientists were able to recreate events that occur before the severe vascular abnormalities seen in postmortem human brain tissue. They could then identify the mechanisms behind those changes and quickly test possible treatments.

APOE4 May Also Disrupt the Brain’s Protein Cleanup

In the Cell Stem Cell study, researchers used miBrains to explore another effect of APOE4: its role in the accumulation of abnormal proteins associated with neurodegenerative disease.

Abnormal protein buildup is a defining feature of conditions such as Alzheimer’s and Parkinson’s disease. However, investigating exactly how these deposits form inside a living human brain is extremely difficult. The miBrain system gives scientists a way to observe related processes in complex human brain-like tissue under laboratory conditions.

miBrains include all of the major cell types present in the human brain, including neurons, supporting glial cells, myelin producing cells, and cells that make up blood vessels. Similar to what happens in the human brain, miBrains carrying APOE4 developed higher amounts of abnormal alpha-synuclein. This protein is most strongly associated with Lewy body dementia and Parkinson’s disease.

Although alpha-synuclein has major clinical importance, researchers have not fully understood the cellular processes that cause it to accumulate.

Cholesterol Buildup Disrupts Cellular Waste Removal

The experiments revealed that APOE4 causes cholesterol to accumulate inside astrocytes, support cells that perform several essential functions in maintaining brain health.

That excess cholesterol interfered with the astrocytes’ lysosomal waste-disposal system. As a result, the cells became less effective at breaking down alpha-synuclein. Instead of being cleared away, the protein accumulated and spread to neurons, where it contributed to harmful deposits.

These findings suggest that cholesterol metabolism inside astrocytes, along with lysosomal function, could become important treatment targets for both Alzheimer’s and Parkinson’s disease.

Using miBrains, the researchers were able to follow the chain of events in complex human brain-like tissue. Their experiments connected APOE4 with lipid buildup in astrocytes, weaker clearance of alpha-synuclein, and the formation of toxic protein deposits.

The results point to both lipid metabolism and cellular waste removal systems as potential therapeutic targets in neurodegenerative disease.

A Platform for Testing Personalized Treatments

Another advantage of the miBrain system is that researchers can preserve the tissue for future experiments.

“A key advance of our technology is that miBrains with predefined cellular compositions and disease-related factors can be cryopreserved,” said Louise Mesentier-Louro, PhD, Assistant Professor of Neuroscience, and Stem Cell Biology and Regenerative Medicine, at the Icahn School of Medicine at Mount Sinai and first author of the Cell Stem Cell study. “This capability improves reproducibility and scalability of complex disease modeling and supports more efficient drug development and validation.”

Mount Sinai researchers are also developing miBrains derived from individual patients, which could eventually allow scientists to investigate how neurodegenerative disease develops differently from person to person and how patients might respond to particular treatments.

“At Mount Sinai we are creating and cryopreserving miBrains from patients,” Dr. Blanchard added. “This will enable personalized studies into how neurodegenerative disease develops and how individuals may respond to therapies. By enabling potential therapies to be tested earlier and more efficiently, the miBrain platform could help bridge the gap between laboratory discoveries and treatments for a broad range of disorders.”

Study Funding

The Cell study examining vascular degeneration in the brain received support from the National Aeronautics and Space Administration (80ARC022CA004), the National Institute on Aging at the National Institutes of Health (R01AG089533, UH3NS115064, U54AG090669, T32GM146636), The SWT Foundation, and the CureAlz Fund.

The Cell Stem Cell study examining abnormal protein buildup in the brain received support from the National Aeronautics and Space Administration (80ARC022CA004), Aligning Science Across Parkinson’s (ASAP-024297) through the Michael J. Fox Foundation for Parkinson’s Research, the National Institute of Neurological Disorders and Stroke and the National Institute on Aging at the National Institutes of Health (R01NS114239, UH3NS115064, 1U54AG090669-01, T32AG04968, F31NS13090), the CureAlz Fund, and The SWT Foundation.