Neurobiological Pathways Linking the Mediterranean Diet to Alzheimer’s Disease Risk

Written by: Phoebe Matthew

Edited by: Celine Cotran, Ava Hargrave, Mali Gilbert, Ellie Sung, and Jade Kim

Illustrated by: Ruiqi Wang

---

Introduction

Over 7 million Americans are living with Alzheimer’s disease [1]. By 2050, the prevalence of dementia is projected to triple across the world [1]. Alzheimer's is not only extremely debilitating but also one of the leading causes of death in older individuals. Despite our constant scientific advances, the deaths due to Alzheimer’s disease continue to increase each year. Advances in research related to biomarkers, which are substances in the brain that indicate early stages of Alzheimer’s and risk for developing dementia, has pushed diagnostic criteria from purely clinical to biological. As a result, individuals with biomarkers for Alzheimer’s disease, the most significant being amyloid β and phosphorylated tau, that have not developed systems yet are considered to be in the preclinical stage of Alzheimer’s. Those in the preclinical stage are considered to have an elevated risk of progressing to symptomatic stages of Alzheimer's disease [2]. When considering this biological definition of Alzheimer’s, which includes individuals who haven’t developed symptoms yet, the estimated prevalence in 2050 is three times higher [2]. However, there are limitations to purely using the biological definition of Alzheimer’s due to the unknown nature of when symptoms may develop or if they ever will. Therefore, Alzheimer’s is often diagnosed using a clinical-biological approach, which integrates information about biomarkers, risk of progression, and clinical symptoms [3]. With Alzheimer’s being the main cause of dementia, there is a need for research not only on treatments, but also prevention, early detection, and slowing disease progression. 

Prevention and treatment of Alzheimer’s at the early stages involves pharmacological and nonpharmacological aspects. When it comes to nonpharmacological approaches, there are significant limitations in the current body of evidence related to the effectiveness of specific lifestyle changes. For example, there is a lack of long term, randomized, controlled experiments. However, prevention through lifestyle changes is important due to the fact that it is much more difficult to treat a person with biomarkers for Alzheimer’s but no cognitive impairment because of the current aggressive treatments and therapies used to slow disease progression [4]. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was one of the first long-term, randomized, controlled experiments that involved individuals at risk for cognitive impairment, and the effectiveness of a multifaceted lifestyle intervention approach on decreasing this risk was studied [2]. The methodology of this experiment included having participants follow guidelines regarding several lifestyle aspects that have been identified to be important for brain health, including a balanced diet, physical exercise, cognitive training and social activities, and vascular and metabolic risk management. The combination of these changes resulted in cognitive benefits for participants at risk for developing Alzheimer’s. This study points to the significance of lifestyle factors when considering Alzheimer’s disease, especially its pre-clinical early stages. When diving deeper into diet in relation to cognitive health, the “Mediterranean diet”, a term coined in 1960,  has been studied worldwide in relation to health and disease. This diet specifically refers to eating habits connected to the traditional areas in the Mediterranean that emphasize olive cultivation have been observed to have high life expectancies and less chronic diseases [5].

Biological Insights into the Impact of the Mediterranean Diet on the Brain 

Although there have been shifts in dietary practices in the Mediterranean region, the traditional Mediterranean diet is classified by the large intake of plant based foods, including vegetables, fruits, breads, beans, nuts, and seeds. Another distinguishing factor is the fact that most of this food is locally grown and scarcely processed. Additionally, this diet is characterized by the high intake of olive oil. Dairy products are largely limited to cheese and yogurt. Moderate consumption of fish and poultry and low consumption of red meat are also key characteristics. Red wine is moderately consumed with meals, pointing to the differences between the Mediterranean diet and other healthy diets. There has been much discussion on the health benefits of the combination of these foods, rather than seeing each component separately [5]. 

Looking deeper into the pathology behind the development and progression of Alzheimer’s disease allows us to draw connections between properties of certain nutrients and specific biological mechanisms in the brain. The amyloid beta protein is a biomarker for Alzheimer’s, meaning it is a substance in the brain that causes neurodegeneration or the destruction of neurons and synapses, which are essential for communication within the brain. This damage has been related to an increase in reactive oxygen in the brain, leading to oxidative stress that further damages cells [6]. Studies done outside living organisms have found links between antioxidants, including vitamin E, vitamin C, and carotenoids, and reduced oxidative stress; however, it is important to note that in clinical studies no decisive evidence has been found [6]. Olive oil, wine, fruits, and vegetables are essential components of the Mediterranean diet and have been proven to have antioxidant properties [7]. 

Further links between the brain and nutrition have been studied as metabolic syndrome corresponds to an increase in risk for cognitive impairment [8]. Metabolic syndrome is a combination of several metabolic abnormalities, which may include elevated blood glucose, high blood pressure, high HDL cholesterol levels, and insulin resistance. There are several biological mechanisms connecting the characteristics of metabolic syndrome and the pathology of Alzheimer’s. High levels of insulin inhibits an enzyme that degrades insulin but also regulates amyloid β, a biomarker of Alzheimer’s disease [8]. Also, high blood sugar can cause oxidative stress in the brain that, as described before, leads to nerve damage. High blood pressure can also cause damage to blood vessels in the brain, which can cause protein to lead through them ultimately contributing to the formation of neuritic plaques and neurofibrillary tangles, which are key characteristics of Alzheimer’s disease [8]. The Mediterranean diet is attributed to moderately lower carbohydrate intake compared to a moderately higher fat intake with the large majority coming from unsaturated fat. These qualities are linked to improvements in insulin sensitivity, blood lipids such as cholesterol levels, and liver function. By preventing metabolic syndrome, the Mediterranean diet may also contribute to cognitive impairment prevention [7].

Alzheimer's pathology is also characterized by inflammation in the brain, which is a result of the immune response in the brain that is facilitated by microglia cells [2]. The amyloid plaques, deposits of amyloid β, and tau phosphorylation triggers microglia activation, which causes inflammation. As amyloid β and tau continue to accumulate, chronic neuroinflammation occurs and worsens cognitive decline [2]. Specific signaling proteins, such as interleukin, are involved in the brain’s immune response and promote inflammation. Several observational and interventional studies have shown an association between higher adherence to the Mediterranean diet and lower levels of these proteins, suggesting an anti-inflammatory effect [7]. A possible explanation for this effect comes from a study on healthy patients, which concluded that tyrosol and caffeic acid, chemical compounds found in extra virgin olive oil and wine, interact with cells that drive the immune response to reduce IL-6 production [7]. Olive oil and wine are fundamental components of the Mediterranean diet.

Amyloid-beta protein accumulation, metabolic dysfunction, and chronic neuroinflammation are all key processes in the pathogenesis and progression of Alzheimer’s disease. Evidence suggests that adherence to a Mediterranean diet may help regulate these harmful biological mechanisms that contribute to neurodegeneration.

Evidence of Neuroprotective Qualities of the Mediterranean Diet and Limitations

 A study which involved 1,393 participants across a time span of 4.5 years identified an association between adhering to the Mediterranean diet and preventing cognitive impairment [6]. The participants in the highest adherence to the Mediterranean diet had a 48% reduced risk of developing Alzheimer’s disease. A metaanalysis analyzed 9 different studies on the Mediterranean diet and Alzheimer’s disease [8]. According to the analysis, these studies indicated that the Mediterranean diet was correlated with a 30% reduction in the risk for Alzheimer’s disease. The long term adherence was also mentioned as a key factor to the preventative effects of the Mediterranean diet [8].

However, there have been experiments that are not consistent with these findings. In a 5 year study involving 1,410 elderly participants found that the correlation between higher adherence to the Mediterranean diet and reduced cognitive impairments was only found when using a specific cognitive, but not with other tests [6]. Over the time of the study, 99 participants developed incident dementia and there was no correlation found between reduced dementia risk and higher adherence to the Mediterranean diet. These results raise questions about the true significance of the Mediterranean diet on cognitive health. 

It is important to recognize the limitations in the experiments regarding the Mediterranean diet. The long term experiments are purely observational meaning they can only provide a correlation rather than a causation. It is extremely difficult to conduct randomised controlled studies on diet, as ensuring the adherence to the specific diet is difficult to control, especially over long periods of time. Additionally, most research regarding the Mediterranean Diet has involved Mediterranean regions or other Western countries, meaning that the conclusions cannot be generalised to populations worldwide [5].

Implications/Future Research

The current body of knowledge provides moderate evidence to support the idea that the Mediterranean diet may prevent and/or slow cognitive decline, specifically related to Alzheimer’s disease. However, more research must be done on the intersection of pharmacological and nonpharmacological treatment plans (such as the Mediterranean diet) for Alzheimer’s disease. The implementation of research in patient-care is extremely important, and currently there is a lack of research regarding inclusion of the Mediterranean diet in treatment strategies for individuals in the various stages of Alzheimer’s. As stated before, research regarding the Mediterranean diet must be expanded to a broader variety of geographical populations to create a more comprehensive understanding of the limitations and implications of the Mediterranean diet and preventing cognitive impairments.

---

References

[1] Alzheimer’s Association. Alzheimer’s disease facts and figures. Published 2025. https://www.alz.org/alzheimers-dementia/facts-figures

[2] Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet. 2021;397(10284):1577-1590. doi:10.1016/S0140-6736(20)32205-4

[3] Dubois B, Villain N, Schneider L, et al. Alzheimer disease as a clinical-biological construct: an International Working Group recommendation. JAMA Neurol. 2024;81(12):1304-1311. doi:10.1001/jamaneurol.2024.3770

[4] Viña J, Sanz-Ros J. Alzheimer’s disease: only prevention makes sense. Eur J Clin Invest. 2018;48(10):e13005. doi:10.1111/eci.13005

[5] Guasch-Ferré M, Willett WC. The Mediterranean diet and health: a comprehensive overview. J Intern Med. 2021;290(3):549-566. doi:10.1111/joim.13333

[6] Sofi F, Macchi C, Abbate R, Gensini GF, Casini A. Effectiveness of the Mediterranean diet: can it help delay or prevent Alzheimer’s disease? J Alzheimers Dis. 2010;20(3):795-801. doi:10.3233/JAD-2010-1418

[7] Frisardi V, Panza F, Seripa D, et al. Nutraceutical properties of Mediterranean diet and cognitive decline: possible underlying mechanisms. J Alzheimers Dis. 2010;22(3):715-740. doi:10.3233/JAD-2010-100942

[8] Florentin M. Metabolic syndrome and Alzheimer’s disease: a link to a vascular hypothesis? CNS Spectr. 2008. doi:10.1017/S1092852900016886