Mediterranean diet may offset genetic risk of Alzheimer's
Researchers found dietary changes may help improve cognitive health and stave off dementia
A new study led by investigators from Mass General Brigham, Harvard T.H. Chan School of Public Health, and the Broad Institute of MIT and Harvard suggests that a Mediterranean-style diet may help reduce dementia risk. The study, published in Nature Medicine, found that people at the highest genetic risk for Alzheimer's disease benefited more from following a Mediterranean-style diet, showing a greater reduction in dementia risk compared to those at lower genetic risk.
"One reason we wanted to study the Mediterranean diet is because it is the only dietary pattern that has been causally linked to cognitive benefits in a randomized trial," said study first author Yuxi Liu, PhD, a research fellow in the Department of Medicine at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, and a postdoctoral fellow at the Harvard Chan School and Broad. "We wanted to see whether this benefit might be different in people with varying genetic backgrounds, and to examine the role of blood metabolites, the small molecules that reflect how the body processes food and carries out normal functions."
Over the last few decades, researchers have learned more about the genetic and metabolic basis of Alzheimer's disease and related dementias. These are among the most common causes of cognitive decline in older adults. Alzheimer's disease is known to have a strong genetic component, with heritability estimated at up to 80%.
One gene in particular, apolipoprotein E (APOE), has emerged as the strongest genetic risk factor for sporadic Alzheimer's disease — the more common type develops later in life and is not directly inherited in a predictable pattern. People who carry one copy of the APOE4 variant have a 3-to-4-fold higher risk of developing Alzheimer's. People with two copies of the APOE4 variant (called APOE4 homozygous) have a 12-fold higher risk of Alzheimer's than those without.
To explore how the Mediterranean diet may reduce dementia risk and influence blood metabolites linked to cognitive health, the team analyzed data from 4,215 women in the Nurses' Health Study, following participants from 1989 to 2023 (average age 57 at baseline). To validate their findings, the researchers analyzed similar data from 1,490 men in the Health Professionals Follow-Up Study, followed from 1993 to 2023.
Researchers evaluated long-term dietary patterns using food frequency questionnaires and examined participants' blood samples for a broad range of metabolites. Genetic data were used to assess each participant’s inherited risk for Alzheimer’s disease. Participants were then followed over time for new cases of dementia. A subset of 1,037 women underwent regular telephone-based cognitive testing.
They found that the people following a more Mediterranean-style diet had a lower risk of developing dementia and showed slower cognitive decline. The protective effect of the diet was strongest in the high-risk group with two copies of the APOE4 gene variant, suggesting that diet may help offset genetic risk.
"These findings suggest that dietary strategies, specifically the Mediterranean diet, could help reduce the risk of cognitive decline and stave off dementia by broadly influencing key metabolic pathways," Liu said. "This recommendation applies broadly, but it may be even more important for individuals at a higher genetic risk, such as those carrying two copies of the APOE4 genetic variant."
A study limitation was that the cohort consisted of well-educated individuals of European ancestry. More research is needed in diverse populations.
In addition, although the study reveals important associations, genetics and metabolomics are not yet part of most clinical risk prediction models for Alzheimer's disease. People often don't know their APOE genetics. More work is needed to translate these findings into routine medical practice.
"In future research, we hope to explore whether targeting specific metabolites through diet or other interventions could provide a more personalized approach to reducing dementia risk," Liu said.
Authorship: In addition to Liu, Mass General Brigham authors include Chirag M. Vyas, Cheng Peng, Danyue Dong, Yuhan Li, Oana A. Zeleznik, Jae H. Kang, Molin Wang, Frank B. Hu, Olivia I. Okereke, A. Heather Eliassen, Meir J. Stampfer, and Dong D. Wang. Additional authors include Xiao Gu, Yanping Li, Fenglei Wang, Yu Zhang, Yin Zhang, Walter C. Willett, and Peter Kraft.
Disclosures: None.
Funding: This study was funded in part by the National Institutes of Health (R00DK119412, R01NR019992, R01AG077489, RF1AG083764, U54AG089325, P30DK046200, UM1CA186107, P01CA087969, R01HL034594, R01HL088521, R01HL060712, U01CA167552, R01HL035464).
Paper cited: Liu Y et al. "Interplay of genetic predisposition, plasma metabolome, and Mediterranean diet in dementia risk and cognitive function" Nature Medicine DOI: 10.1038/s41591-025-03891-5
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About Mass General Brigham
Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation's leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org.
Journal
Nature Medicine
Method of Research
Observational study
Subject of Research
People
Article Title
Interplay of genetic predisposition, plasma metabolome, and Mediterranean diet in dementia risk and cognitive function
Mediterranean diet with fewer calories and exercise lowers diabetes risk by 31%
PREDIMED-Plus, a Spanish multicenter clinical trial in which the University of Navarra participates, demonstrates that modest, sustained changes in diet and lifestyle can prevent thousands of cases of diabetes worldwide
image:
From left to right: Drs. Miguel Ángel Martínez and Miguel Ruíz-Canela.
view moreCredit: Manuel Castells/Miriam Salcedo
Pamplona (Spain), August 25. Eating Mediterranean-style, but with fewer calories, more moderate exercise, and professional support for weight loss, reduces the risk of developing type 2 diabetes by 31%. This is the main finding of PREDIMED-Plus, a large Spanish multicenter clinical trial in which the University of Navarra is participating in collaboration with more than 200 researchers from 22 other Spanish universities, hospitals, and research centers, and conducted in over 100 primary care centers of the Spanish National Health System.
This is the largest European trial on nutrition, initiated in 2013 by the University of Navarra thanks to the award of an Advanced Grant from the European Research Council (ERC) of more than €2 million. Subsequently, between 2014 and 2016, the rest of the institutions joined the trial reaching an overall funding of more than 15 million euros, provided mainly by the Carlos III Health Institute (ISCIII) and the Center for Biomedical Research Network (CIBER) through its areas of Physiopathology of Obesity and Nutrition (CIBEROBN), Epidemiology and Public Health (CIBERESP) and Diabetes and Associated Metabolic Diseases (CIBERDEM ).
The study, published in Annals of Internal Medicine, followed 4,746 people aged 55 to 75 years with overweight or obesity and metabolic syndrome, with no history of cardiovascular disease or diabetes, for six years. To evaluate whether an optimized version of the Mediterranean diet could reinforce the prevention of type 2 diabetes, researchers compared two groups: one adopted a calorie-reduced Mediterranean diet (about 600 kcal fewer per day), a moderate exercise plan (brisk walking, strength and balance training), and professional guidance; the other followed the traditional Mediterranean diet, without calorie restriction or exercise advice.
Results show that, beyond reducing diabetes risk, the intervention group lost an average of 3.3 kg and reduced waist circumference by 3.6 cm, compared to just 0.6 kg and 0.3 cm in the control group. In practical terms, this meant preventing approximately three in every 100 participants from developing type 2 diabetes—a significant public health benefit.
"Diabetes is the first solid clinical outcome for which we have shown —using the strongest available evidence —that the Mediterranean diet with calorie reduction, physical activity and weight loss is a highly effective preventive tool,” said Miguel Ángel Martínez-González, Professor of Preventive Medicine and Public Health at the University of Navarra, Adjunct Professor of Nutrition at Harvard University, and one of the principal investigators of the project. “Applied at scale in at-risk populations, these modest and sustained lifestyle changes could prevent thousands of new diagnoses every year. We hope soon to show similar evidence for other major public health challenges.”
Type 2 Diabetes: A Preventable Global Epidemic
Type 2 diabetes now affects more than 530 million people worldwide, according to the latest data from the International Diabetes Federation. Its rapid growth is driven by urbanisation (unhealthy diets, sedentary lifestyles, reduced physical activity), an ageing population, and rising rates of overweight and obesity. In Spain, where some 4.7 million adults live with diabetes (most of them type 2), the disease has one of the highest rates in Europe, where there are more than 65 million people with diabetes. In the United States, the figure is approximately 38.5 million, and the prevalence far exceeds the global average, with one of the highest healthcare costs per patient worldwide. Experts warn that prevention is essential to curb this public health emergency, which significantly increases the risk of cardiovascular, renal, and metabolic complications.
"The Mediterranean diet acts synergistically to improve insulin sensitivity and reduce inflammation. With PREDIMED-Plus, we demonstrate that combining calorie control and physical activity enhances these benefits,” explained Miguel Ruiz-Canela, Professor and Chair of Preventive Medicine and Public Health Department at the University of Navarra’s School of Medicine and first author of the study. “It is a tasty, sustainable and culturally accepted approach that offers a practical and effective way to prevent type 2 diabetes—a global disease that is, to a large extent, avoidable.”
International Relevance and Support for a Realistic and Scalable Strategy
Annals of Internal Medicine accompanied the publication with an editorial by Sharon J. Herring and Gina L. Tripicchio, nutrition and public health experts at Temple University (Philadelphia, USA). They praised the intervention’s clinical relevance and its potential as a preventive model for type 2 diabetes. Furthermore, they warn that replicating similar strategies outside the Mediterranean context—such as in the U.S.—requires overcoming structural barriers, including unequal access to healthy foods, the limitations of the urban environment, and the lack of professional guidance. In this scenario, they advocate strengthening public policies that promote more nutritious and more equitable environments. At a time when new drugs against obesity and diabetes are grabbing headlines, PREDIMED-Plus demonstrates that modest, sustained lifestyle changes can still deliver powerful health benefits.
The PREDIMED-Plus project (2013-2024), which involves different patients, is a continuation of the PREDIMED study (2003-2010). This study demonstrated that following a Mediterranean diet enriched with extra-virgin olive oil or nuts reduces the risk of cardiovascular disease by 30%. Researchers emphasize that primary care providers can integrate the new intervention as a sustainable, cost-efficient strategy to prevent type 2 diabetes on a large scale.
Participating Institutions
The PREDIMED-Plus trial has assembled a broad network of investigators from across Spain. In order of the number of participants, the study included researchers from the following institutions: the University of Navarra and the Navarra Health Service (2 centers), Hospital Clínic de Barcelona (2 centers), University of Valencia, Rovira i Virgili University (Reus), IMIM-Hospital del Mar, Miguel Hernández University (Alicante), Son Espases Hospital (Palma de Mallorca), University of Malaga, Reina Sofía Hospital (Córdoba) and University of Granada. In addition, Bioaraba and the UPV/EHU (Vitoria), the University of the Balearic Islands, the Hospital Virgen de la Victoria (Malaga), the University of Las Palmas de Gran Canaria, the University of Leon, the Primary Health Care District of Seville, the Fundación Jiménez Díaz (Madrid), the Hospital de Bellvitge, the Hospital Clínico San Carlos (Madrid), the University of Jaen, and the IMDEA Food Institute (Madrid) have also participated.
The project also benefited from international collaboration with the Harvard T.H. Chan School of Public Health (USA). Most of the participating researchers are affiliated with the CIBEROBN, CIBERESP, or CIBERDEM research networks.
Journal
Annals of Internal Medicine
Method of Research
Randomized controlled/clinical trial
Subject of Research
People
Article Title
Comparison of an energy-reduced Mediterranean diet and physical activity versus an ad libitum Mediterranean diet in the prevention of type 2 diabetes: A secondary analysis of a randomized controlled trial
Article Publication Date
26-Aug-2025
Mediterranean diet combined with calorie reduction and exercise may reduce risk of type 2 diabetes by nearly one-third
Harvard T.H. Chan School of Public Health
Key points:
- Those who adhered to a Mediterranean diet, reduced their caloric intakes, engaged in moderate exercise, and received professional weight loss support had a 31% lower risk of developing type 2 diabetes compared to those who adhered to a Mediterranean diet alone.
- The findings come from PREDIMED-Plus, the largest nutrition and lifestyle clinical trial ever conducted in Europe.
Boston, MA—A Mediterranean-style diet, in combination with reduced caloric intake, moderate physical activity, and professional support for weight loss, may cut the risk of type 2 diabetes (T2D) by 31%, according to a new study co-authored by researchers at Harvard T.H. Chan School of Public Health.
The study will be published August 25, 2025, in the Annals of Internal Medicine.
“We’re facing a global epidemic of diabetes,” said co-author Frank Hu, Fredrick J. Stare Professor of Nutrition and Epidemiology and chair of the Department of Nutrition. “With the highest-level evidence, our study shows that modest, sustained changes in diet and lifestyle could prevent millions of cases of this disease worldwide.”
Prior research has linked the Mediterranean diet—which emphasizes high intake of fruits, vegetables, whole grains, and healthy fats, moderate intake of dairy and lean proteins, and little to no intake of red meat—to better health outcomes, including lowered risk of T2D through improved insulin sensitivity and reduced inflammation.
A team of collaborators from the PREDIMED-Plus clinical trial, the largest nutrition and lifestyle randomized trial in Europe, sought to understand how the diet’s benefits may be enhanced with additional healthy lifestyle changes.
The researchers, from 23 universities in Spain and Harvard Chan School, split 4,746 PREDIMED-Plus participants into an intervention group and a control group and followed their health outcomes for six years. The intervention group adhered to a Mediterranean diet; reduced their caloric intake by about 600 calories per day; engaged in moderate physical activity, such as brisk walking and strength and balance exercises; and received professional support for weight loss control. The control group adhered to a Mediterranean diet without calorie restriction, exercise guidance, or professional support. Participants ranged from age 55 to 75, were overweight or obese, and had metabolic syndrome, but were free of T2D at baseline.
The study found that those in the intervention group had a 31% lower risk of developing T2D compared to those in the control group. Additionally, the intervention group lost an average of 3.3 kilograms and reduced their waist circumference by 3.6 centimeters, compared to 0.6 kilograms and 0.3 centimeters in the control group.
“In practical terms, adding calorie control and physical activity to the Mediterranean diet prevented around three out of every 100 people from developing diabetes—a clear, measurable benefit for public health,” said co-author Miguel Martínez-González, professor at the University of Navarra and adjunct professor of nutrition at Harvard Chan School.
The study was funded by the European Research Council, the Spanish National Institute of Health, the Biomedical Research Networking Centre (CIBER), and the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK127601).
“Comparison of an Energy-Reduced Mediterranean Diet and Physical Activity Versus an Ad Libitum Mediterranean Diet in the Prevention of Type 2 Diabetes,” Miguel Ruiz-Canela, Dolores Corella, Miguel Ángel Martínez-González, Nancy Babio, J. Alfredo Martínez, Luis Forga, Ángel M. Alonso-Gómez, Julia Wärnberg, Jesús Vioque, Dora Romaguera, José López-Miranda, Ramón Estruch, José Manuel Santos-Lozano, Luis Serra-Majem, Aurora Bueno-Cavanillas, Josep A. Tur, Vicente Martín-Sánchez, Antoni Riera-Mestre, Miguel Delgado-Rodríguez, Pilar Matía-Martín, Josep Vidal, Clotilde Vázquez, Lidia Daimiel, Pilar Buil-Cosiales, Sangeetha Shyam, Jose V. Sorlí, Olga Castañer, Antonio García-Rios, Laura Torres-Collado, Enrique Gómez-Gracia, M. Ángeles Zulet, Jadwiga Konieczna, Rosa Casas, Naomi Cano-Ibáñez, Lucas Tojal-Sierra, Rosa M. Bernal-López, Estefanía Toledo, Jesús García-Gavilán, Rebeca Fernández-Carrión, Albert Goday, Antonio P. Arenas-Larriva, Sandra González-Palacios, Helmut Schröder, Emilio Ros, Montserrat Fitó, Frank B. Hu, Francisco J. Tinahones, Jordi Salas-Salvadó, the Annals of Internal Medicine, August 25, 2025, doi: 10.7326/ANNALS-25-00388
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Harvard T.H. Chan School of Public Health is a community of innovative scientists, practitioners, educators, and students dedicated to improving health and advancing equity so all people can thrive. We research the many factors influencing health and collaborate widely to translate those insights into policies, programs, and practices that prevent disease and promote well-being for people around the world. We also educate thousands of public health leaders a year through our degree programs, postdoctoral training, fellowships, and continuing education courses. Founded in 1913 as America’s first professional training program in public health, the School continues to have an extraordinary impact in fields ranging from infectious disease to environmental justice to health systems and beyond.
Journal
Annals of Internal Medicine
Method of Research
Randomized controlled/clinical trial
Subject of Research
People
Article Title
Comparison of an Energy-Reduced Mediterranean Diet and Physical Activity Versus an Ad Libitum Mediterranean Diet in the Prevention of Type 2 Diabetes
Article Publication Date
25-Aug-2025
