What this is
- Neurodegenerative diseases like Alzheimer's and Parkinson's pose significant public health challenges.
- The (MedDiet), rich in fruits, vegetables, and , may slow cognitive decline.
- This review integrates evidence on how the MedDiet, particularly its like resveratrol and oleuropein, influences neurodegenerative disease progression.
Essence
- The is associated with slower cognitive decline and reduced risk of neurodegenerative diseases. , especially resveratrol and oleuropein, are key components that may mediate these protective effects.
Key takeaways
- Higher adherence to the correlates with slower cognitive decline. Epidemiological studies suggest that individuals closely following this diet have a lower risk of developing Alzheimer's disease and Parkinson's disease.
- like resveratrol and oleuropein exhibit neuroprotective effects through mechanisms such as antioxidant activity and modulation of amyloid aggregation. These compounds may enhance mitochondrial function and reduce neuroinflammation.
- Current clinical studies indicate potential cognitive benefits from polyphenol-rich interventions, though further long-term trials are necessary to establish causal relationships and optimize dietary recommendations.
Caveats
- Much of the mechanistic evidence comes from in vitro or animal studies, with limited long-term human data. The low daily intake of from a typical may not fully account for observed cognitive benefits.
- Variability in dietary assessment methods and self-reported intake can introduce bias. Differences in individual metabolism and gut microbiome composition may also affect the outcomes.
- The review emphasizes the need for larger, multicenter trials to clarify causal pathways and the effectiveness of polyphenol-rich diets in neurodegenerative disease prevention.
Definitions
- Mediterranean diet: A dietary pattern characterized by high intake of fruits, vegetables, whole grains, legumes, fish, and olive oil, with moderate dairy and low red meat consumption.
- polyphenols: A group of bioactive compounds found in plants that exhibit antioxidant and anti-inflammatory properties, potentially influencing neurodegenerative processes.
Simplified
1. Introduction
Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are among the most pressing public health challenges worldwide [1,2,3,4,5]. Their prevalence increases steeply with age, and they contribute substantially to disability, loss of independence, and premature mortality [2]. Although pharmacological therapies continue to advance, current treatments have only modest effects on slowing disease progression, and none provide meaningful disease modification [6,7,8,9,10]. As a result, there is growing emphasis on identifying preventive and adjunctive strategies that may preserve cognitive function and delay neurodegenerative processes across the lifespan [11,12,13,14].
Dietary patterns have emerged as one of the most influential and modifiable determinants of brain aging [3,15,16,17,18,19,20,21,22,23,24,25]. Among them, the Mediterranean diet (MedDiet) has received particular attention [3,15,17,19,20,23,26,27]. Characterized by high intake of fruits, vegetables, legumes, whole grains, nuts, fish, and extra virgin olive oil; moderate consumption of dairy products and wine; and low intake of red and processed meats, the MedDiet represents a nutrient-dense, anti-inflammatory, and metabolically favorable dietary pattern [14,27,28,29,30,31,32,33,34,35,36]. Numerous epidemiological and interventional studies have linked the MedDiet to improved cardiovascular and metabolic health and to better cognitive performance in older adults [15,27,29,37,38,39,40,41,42].
Within the MedDiet, polyphenols have been proposed as key contributors to neuroprotection [13]. Among these, resveratrol—abundant in grapes, berries and red wine [43,44,45]—and oleuropein—characteristic of olives and olive oil [46,47]—have attracted particular interest. Experimental and clinical studies suggest that these compounds exert antioxidant [48,49,50,51,52,53], anti-inflammatory [43,54,55,56,57], and neuroprotective effects, influence mitochondrial function [58,59,60,61,62], and modulate protein aggregation pathways relevant to Alzheimer's and Parkinson's disease [63,64,65]. They also activate key signaling cascades involved in cellular stress resistance and brain aging, including SIRT1 [66,67,68,69,70,71].
The aim of this narrative review is to summarize current evidence on the Mediterranean diet and the progression of neurodegenerative diseases, with particular focus on polyphenols—especially resveratrol and oleuropein—as potential mediators of these associations. By integrating epidemiological findings, clinical trial data, and mechanistic insights, the review highlights how the MedDiet may influence neurodegenerative trajectories and discusses key areas where further research is needed to refine preventive and therapeutic applications.
2. Methods
2.1. Literature Search
The literature search was conducted in the PubMed, Scopus, and Web of Science databases, covering the period from January 2010 to August 2025. The following keywords and their combinations were used: "Mediterranean diet," "neurodegenerative diseases," "Alzheimer's disease," "Parkinson's disease," "cognitive decline," "polyphenols," "resveratrol," "oleuropein," "oxidative stress," and "neuroprotection." This search initially yielded 5732 records (PubMed: 1856; Scopus: 1944; Web of Science: 1932). After removing 1324 duplicates, 4408 records remained for screening. Titles and abstracts were screened for relevance, leading to the exclusion of 4212 studies that did not meet the inclusion criteria. The full texts of 196 studies were assessed for eligibility, and 70 studies were ultimately included in the qualitative synthesis. The search was further supplemented by manual screening of references cited in relevant reviews and clinical studies.
2.2. Inclusion Criteria
Studies were considered eligible if they met the following criteria: Population: Human studies related to neurodegenerative diseases or cognitive decline. Intervention/exposure: Examination of the Mediterranean diet as a whole or its key bioactive components [e.g., resveratrol, oleuropein, other polyphenols]. Outcomes: Incidence or progression of neurodegenerative diseases, changes in cognitive function, or biomarkers [e.g., oxidative stress, inflammatory markers, amyloid and tau pathology]. Study types: Randomized controlled trials (RCTs), prospective and retrospective cohort studies, and cross-sectional studies, but not experimental [in vivo or in vitro] research.
2.3. Exclusion Criteria
The following were excluded: Publications without original data [editorials, letters, conference abstracts]. Studies not related to neurodegenerative diseases or cognitive outcomes. Studies investigating isolated nutrients outside the context of the Mediterranean diet. Animal or other preclinical studies.
2.4. Data Extraction and Synthesis
From each eligible study, we extracted information on authorship, publication year, study population, sample size, exposure or intervention, outcomes, and key results. Evidence was synthesized narratively and grouped into the following themes: Epidemiological associations between the Mediterranean diet and cognitive decline or neurodegenerative diseases. Findings from clinical trials of Mediterranean diet-based interventions. Mechanistic insights focusing on polyphenols, particularly resveratrol and oleuropein. Remaining knowledge gaps and directions for future research.
2.5. Quality Assessment and Limitations
As a narrative review, no formal quality appraisal tool was applied. However, when interpreting the literature, we prioritized studies with strong methodological design, adequate sample size, and longer follow-up. Potential biases, heterogeneity across studies, and publication bias were taken into consideration.
2.6. Aim of the Review
The aim of this narrative review is to synthesize current evidence on how the Mediterranean diet may influence the progression of neurodegenerative diseases, with particular emphasis on the potential contributions of polyphenols such as resveratrol and oleuropein.
It is important to emphasize that focusing on resveratrol and oleuropein does not imply that these compounds are the sole or principal drivers of the Mediterranean diet's neuroprotective effects. Dietary intake levels of both molecules are generally very low, and the concentrations used in mechanistic studies—particularly in vitro and animal models—often exceed those achievable through habitual Mediterranean dietary patterns. Their inclusion in this review reflects their status as two of the most extensively investigated bioactive constituents of the diet, rather than exclusive mediators of its benefits. Accordingly, the relevance of these mechanistic pathways to human physiology is limited by substantial dose discrepancies, and the evidence presented should be interpreted as supporting biological plausibility rather than direct proof of efficacy at dietary exposure levels. The overall neuroprotective potential of the Mediterranean diet is more likely to stem from synergistic interactions among multiple dietary components—including other olive-derived phenolics, monounsaturated fatty acids, antioxidant- and fiber-rich plant foods, and gut–brain axis-mediated metabolic effects. Therefore, the discussion of resveratrol and oleuropein serves primarily as an illustrative framework for understanding specific mechanistic pathways, without overstating their isolated importance.
3. Mechanistic Basis: How the Mediterranean Diet May Slow Neurodegeneration
The neuroprotective effects of the MedDiet arise from a constellation of biological mechanisms supported by its nutrient composition and bioactive compounds. These mechanisms provide a rationale for epidemiological observations linking the MedDiet to slower cognitive decline and reduced neurodegenerative risk. Table 1 provides a comparative overview of key dietary patterns, highlighting the nutrients and bioactive compounds that may influence neurodegenerative processes.
3.1. Anti-Inflammatory Effects
Chronic low-grade inflammation is a central driver of neurodegenerative diseases [72,73,74,75], and several components of the MedDiet act to counter this process [23,76,77,78,79]. The diet's high content of omega-3 fatty acids, olive oil phenolics, polyphenols, carotenoids, and dietary fiber contributes to lower circulating levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Additional micronutrients—including zinc, magnesium, and calcium—support immune regulation. Extra virgin olive oil provides phenolic compounds such as oleocanthal, oleacein, and oleic acid, which inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related inflammatory pathways and platelet activation. By engaging these complementary pathways, the MedDiet reduces systemic inflammation and may thereby mitigate neuroinflammatory cascades implicated in cognitive decline and neurodegeneration [80].
3.2. Antioxidant Effects and Protection Against Protein Misfolding
Oxidative stress is a key mediator of neuronal injury, protein misfolding, and synaptic dysfunction in Alzheimer's and Parkinson's disease [81,82,83,84]. The MedDiet's rich supply of polyphenols, vitamins E and C, and carotenoids enhances cellular antioxidant capacity and reduces reactive oxygen species (ROS) [85,86,87,88]. Polyphenols play a particularly important role, as their antioxidant and anti-inflammatory properties counteract protein aggregation processes linked to the formation of amyloid-β and α-synuclein deposits, which are central features of Alzheimer's and Parkinson's disease pathophysiology. Experimental models have demonstrated that resveratrol promotes amyloid-β degradation through proteasomal and autophagosomal pathways, increases the activity of degrading enzymes such as neprilysin, and inhibits the pathological hyperphosphorylation of tau protein. Furthermore, resveratrol directly interferes with Aβ aggregation and facilitates the formation of non-toxic conformations. Similarly, quercetin enhances AMPK activity and reduces tau hyperphosphorylation, while other flavonoids—including anthocyanins and caffeic acid derivatives—exert neuroprotective effects by attenuating oxidative stress and protein aggregation. Collectively, these mechanisms enhance neuronal resilience against toxic protein accumulation and ROS-induced damage, thereby highlighting the antioxidant components of the MedDiet as key contributors to the slowing of neurodegenerative processes [89].
3.3. Support of Mitochondrial Function
Mitochondrial dysfunction is a recognized early event in the pathogenesis of Alzheimer's and Parkinson's disease, contributing to impaired energy metabolism, increased oxidative stress, and heightened neuronal vulnerability [90,91,92,93,94,95,96,97,98,99]. Bioactive components of the Mediterranean diet—including resveratrol and major polyphenols from extra virgin olive oil (EVOO), such as hydroxytyrosol, oleuropein, and oleocanthal—play a crucial role in maintaining mitochondrial health [76,100,101]. These compounds activate key energy-regulating pathways, including AMP-activated protein kinase (AMPK), sirtuin-1 (SIRT1), and the mechanistic target of rapamycin (mTOR), which converge on transcriptional regulators of mitochondrial biogenesis such as peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), nuclear respiratory factor-1 (NRF1), and mitochondrial transcription factor A (TFAM) [66,102,103,104,105,106]. Through these pathways, they stimulate the formation of new mitochondria, enhance ATP production, and help maintain mitochondrial DNA stability [59,60,61,62,67,107,108,109]. Experimental studies consistently show that EVOO polyphenols increase ATP levels, improve respiratory chain complex activity, and restore oxidative phosphorylation efficiency. In parallel, EVOO-derived phenolics reduce mitochondrial ROS generation, strengthen endogenous antioxidant defenses, and activate the Nrf2-dependent vitagene network, leading to increased expression of cytoprotective enzymes such as superoxide dismutase and catalase. By also suppressing NF-κB-mediated inflammatory signaling, they blunt both oxidative and inflammatory stress in cells of the neurovascular unit [43,58,66,105,110,111,112,113,114]—two interlinked drivers of neurodegenerative pathology. Beyond these effects, EVOO polyphenols promote mitophagy, stabilize mitochondrial membrane structure and fluidity, and support a healthy balance between mitochondrial fusion and fission. Together, these actions counteract age- and metabolism-related mitochondrial dysfunction. Because neurons depend heavily on efficient mitochondrial function, these mechanisms are likely to contribute substantially to the neuroprotective effects of the Mediterranean diet [115]. It is important to note that certain mechanistic elements presented in this section overlap with those discussed in Section 3.4, as mitochondrial and vascular processes are biologically tightly interconnected.
3.4. Improvement of Vascular and Metabolic Health
Vascular dysfunction [116,117,118,119,120,121] and metabolic impairment [23,72,122,123] are major contributors to Alzheimer's disease and cognitive decline [124,125,126,127,128], influencing cerebral perfusion, blood–brain barrier integrity, insulin signaling, and the accumulation of amyloid and tau pathology. The MedDiet favorably modulates glucose and insulin metabolism [23,35,87], enhances endothelial and neurovascular function [129,130,131,132,133,134], and reduces the risk of atherosclerosis. These improvements support cerebral blood flow and neuronal energy supply and mitigate vascular contributions to cognitive impairment and dementia. The MedDiet's emphasis on plant-based foods—fruits, vegetables, legumes, whole grains, and nuts—provides antioxidants, anti-inflammatory nutrients, and fiber that collectively reduce insulin resistance, endothelial dysfunction, and cardiovascular risk. Polyphenols play a particularly important role: compounds such as resveratrol, quercetin, catechins, and ellagic acid help maintain vascular homeostasis by increasing endothelial nitric oxide availability, reducing adhesion molecule expression (ICAM-1, VCAM-1), and lowering inflammatory cytokines, including TNF-α and IL-6 [61,110,111,112,114,129,135,136,137,138,139,140,141,142,143,144,145,146]. Together, these mechanisms slow vascular aging by limiting oxidative stress, reducing endothelial senescence and telomere-related damage, and dampening vascular inflammation. By preserving endothelial function, improving metabolic control, and lowering cardiometabolic risk factors, the MedDiet supports cardiovascular health and, indirectly, contributes to reducing neurodegenerative risk and progression [25,147].
Functional brain connectivity is increasingly recognized as a key mechanistic component of Alzheimer's disease and age-related cognitive decline [148,149,150,151,152,153,154]. Neurodegeneration disrupts large-scale neural networks—particularly the default mode, frontoparietal, and hippocampal networks—leading to impaired synchronization between regions that support memory, executive function, and attention. Resting-state fMRI studies consistently show reduced connectivity within the default mode network and altered hippocampal–prefrontal coupling even in early or preclinical AD stages [148,149,151,152,153]. Emerging evidence suggests that dietary patterns such as the Mediterranean diet may influence these network-level alterations [155,156]. Interventions enriched with polyphenols have been shown to enhance hippocampal functional connectivity [157] and improve cerebrovascular responsiveness and neurovascular coupling [51]. These findings raise the possibility that diet-induced modulation of neurovascular and metabolic pathways may partly restore or preserve functional network integrity, offering a complementary mechanism through which the Mediterranean diet could slow cognitive decline.
3.5. Gut–Brain Axis and Microbiome Modulation
The Mediterranean diet, rich in fiber, prebiotic compounds, and polyphenols, promotes a favorable gut microbial profile characterized by greater microbial diversity and increased production of short-chain fatty acids (SCFAs), especially butyrate [77,158]. These metabolites exert systemic effects that extend to the central nervous system by strengthening blood–brain barrier function, modulating innate and adaptive immune responses, and supporting neuronal energy metabolism. Butyrate and propionate, in particular, reduce inflammatory signaling, promote microglial homeostasis, and enhance mitochondrial efficiency. The MedDiet is associated with a microbiota composition enriched in beneficial butyrate-producing species such as Faecalibacterium prausnitzii, Eubacterium rectale, and Roseburia spp., while reducing proinflammatory or dysbiotic taxa [77,158,159,160,161,162,163,164]. Functional microbial outputs are equally important: SCFAs generated from the fermentation of dietary fibers and complex carbohydrates enhance regulatory T cell activity, lower systemic low-grade inflammation, and attenuate neuroinflammatory processes that contribute to neurodegenerative progression. Polyphenols and other plant-derived compounds further shape microbiome composition and activity. Phenolic constituents of olive oil, nuts, and red wine are metabolized by gut bacteria into bioactive derivatives with antioxidant and neuromodulatory effects. These metabolites promote the growth of Bifidobacterium and Akkermansia species and inhibit opportunistic pathogens such as Ruminococcus gnavus, which has been linked to increased gut permeability, metabolic endotoxemia, and systemic inflammation [77]. Overall, the MedDiet exerts a dual influence on the gut–brain axis: it shifts microbiome composition toward anti-inflammatory, SCFA-producing communities and increases the generation of metabolites that support neuronal health. These interrelated effects contribute to improved neuroprotection, preserved cognitive function, and a slower trajectory of neurodegenerative processes. It is important to note that much of the mechanistic evidence comes from in vitro or animal models, where the concentrations of polyphenols—particularly resveratrol and oleuropein—often exceed levels achievable through a typical Mediterranean diet. Direct biomarker-level evidence from human studies is limited, and daily dietary intake is far lower than experimental doses. Therefore, these mechanisms should be interpreted as providing biological plausibility rather than direct proof of effects at physiologically relevant dietary levels. Taken together, these mechanisms highlight the central role of the gut–brain axis in mediating the neuroprotective effects of the Mediterranean diet, and Figure 1 summarizes these interconnected pathways.
4. Polyphenols as Key Mediators
A defining feature of the Mediterranean diet is its high content of polyphenol-rich foods. Polyphenols influence several biological pathways relevant to neurodegeneration, including oxidative stress responses, inflammatory signaling, mitochondrial function, and protein aggregation dynamics. Below, we summarize the most extensively studied representatives.
4.1. Resveratrol
Resveratrol, a stilbenoid polyphenol abundant in grapes, berries and red wine, is among the most widely studied natural compounds in the context of Alzheimer's disease [165,166,167,168,169,170,171,172,173]. Its neuroprotective actions are mediated through multiple interconnected mechanisms [174,175,176,177,178,179,180]. Its neuroprotective effects are mediated through multiple mechanisms: it reduces ROS through antioxidant and redox-regulating activity, restores glutathione levels, and activates antioxidant enzymes; SIRT1 activation inhibits NF-κB signaling, attenuates microglial overactivation, and supports neuronal survival; additionally, it modulates the AMPK/PGC-1α/mTOR pathways, enhances mitochondrial biogenesis, and optimizes ATP production. Resveratrol also reduces amyloid-β aggregation, mitigates tau hyperphosphorylation, regulates Cu2+, Zn2+, and Fe2+ homeostasis, and stimulates the expression of neurotrophic factors such as BDNF, NGF, and NT-3. Its anti-inflammatory effects are mediated through inhibition of MAPK and STAT1/3 signaling and suppression of iNOS and COX-2, while additional mechanisms include the induction of autophagy, activation of the Nrf2/HO-1/NQO1 pathway, and reduction in cholinesterase activity [71].
In cellular models, resveratrol attenuates Aβ1-42-induced mitochondrial damage and oxidative stress, promotes PGC-1α deacetylation via AMPK-dependent mechanisms, and activates the SIRT1 pathway, which inhibits NF-κB signaling, reduces proinflammatory cytokine (TNF-α, IL-1β, IL-6) production, and protects against microglial overactivation [181,182]. In animal studies, resveratrol has demonstrated multiple neuroprotective effects, including reduction in Aβ accumulation, decreased lipid peroxidation, enhanced expression of antioxidant enzymes, and improvement of spatial memory [183,184,185]. Furthermore, it stimulates the expression of neurotrophic factors in the nervous system, such as BDNF, NGF, and NT-3, promoting neurogenesis, neuronal survival, and cognitive function [186,187].
Although clinical studies have been limited by small sample sizes and short durations, they suggest that resveratrol can cross the blood–brain barrier and favorably modulate oxidative stress and inflammatory biomarkers, while potentially reducing Aβ accumulation [188,189,190]. Some studies, however, reported adverse effects such as weight loss, nausea, or diarrhea. Confirmation of long-term cognitive benefits requires further investigation. Due to its low bioavailability, pharmacokinetics, drug interactions, and formulation are critical factors for the clinical efficacy of resveratrol.
4.2. Olive Oil Polyphenols and Their Neuroprotective Effects
The extra virgin olive oil (EVOO) contains several potent phenolic compounds, most notably oleuropein (OLE), hydroxytyrosol (HT), and oleocanthal (OLC) [191]. These molecules exhibit strong antioxidant and anti-inflammatory properties and influence multiple pathways implicated in neurodegeneration [192,193]. Preclinical studies show that HT and OLE aglycone can cross the blood–brain barrier, while OLC enhances Aβ clearance and reduces neurotoxic aggregation [11,194,195].
Mechanistically, EVOO polyphenols activate the Nrf2/ARE antioxidant signaling pathway, increase expression of neurotrophic factors (BDNF, NGF), inhibit inflammatory mediators (NF-κB, iNOS, COX-2), attenuate mitochondrial dysfunction, and prevent apoptosis in oxidative stress-induced injury models [64]. These mechanisms parallel, and in some cases complement, those observed for resveratrol.
In vitro and in vivo studies across models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis consistently demonstrate reduced oxidative stress, less neuronal damage, and decreased inflammation associated with these compounds [64]. Clinical data—including findings from PREDIMED [196] and the MICOIL pilot study [197]—suggest that high-polyphenol EVOO improves cognitive performance, reduces blood–brain barrier permeability, lowers neurotoxic Aβ levels, and may slow cognitive decline. These results support the concept that regular EVOO consumption meaningfully contributes to the neuroprotective profile of the Mediterranean diet.
4.3. Other Polyphenols and Bioactive Compounds in the Mediterranean Diet
Beyond olive oil and resveratrol, the Mediterranean diet incorporates a wide array of other polyphenol-rich foods, including citrus fruits, berries, pomegranate, grapes, spices containing curcumin, and green tea rich in catechins [198,199]. These compounds exhibit antioxidant and anti-inflammatory effects and can modulate microglial activation, thereby reducing neuroinflammatory processes.
Many polyphenols also support synaptic function and cognitive resilience. Preclinical studies indicate that flavonoids, catechins, and curcumin enhance neuronal antioxidant defenses—often via Nrf2/ARE pathway activation—and increase levels of neurotrophic factors such as BDNF and NGF. These mechanisms promote synaptic plasticity, neuronal survival, and regeneration [200].
While clinical evidence in humans is still emerging, epidemiological data and animal experiments consistently support the neuroprotective potential of these bioactive compounds. Long-term consumption of polyphenol-rich foods within the framework of the Mediterranean diet may therefore contribute to healthy cognitive aging and reduce the risk of neurodegenerative diseases such as Alzheimer's and Parkinson's disease [201].
5. Mediterranean Diet and Neurodegeneration: Epidemiological Evidence
5.1. Cognitive Decline and Global Cognitive Performance
The relationship between the Mediterranean diet and cognitive function has been investigated in numerous epidemiological and interventional studies over the past decades [202,203,204,205,206,207,208,209,210,211,212]. Several prospective cohort studies have examined the associations between dietary patterns and the risk of dementia, mild cognitive impairment, or general cognitive decline in adults of various ages and sexes [210,211,212]. The results are mixed: some studies did not find a significant association between adherence to the Mediterranean diet and the risk of cognitive decline [210,213], whereas others reported beneficial effects, particularly for memory and global cognition [208,209].
Studies using a metabolomics approach, which assessed adherence to the Mediterranean diet based on biomarkers, also support its potential neuroprotective effects [214]. In cohort studies, higher adherence to the Mediterranean diet was especially associated with a reduced risk of cognitive decline in older women [215,216,217]. Clinical interventions, such as the PREDIMED and PREDIMED-NAVARRA trials, have demonstrated in randomized controlled settings that supplementing the Mediterranean diet with extra virgin olive oil or nuts significantly improves memory, executive functions, and overall cognitive performance compared to control groups [196,218]. Similarly, studies evaluating Mediterranean diet adherence have reported beneficial effects on memory, language, and visuospatial abilities, as well as mental health and quality of life [31,208,219].
Overall, current evidence suggests that the Mediterranean diet, particularly when enriched with antioxidant-rich supplements, may help maintain cognitive function in older age and reduce the risk of dementia. However, the effects appear to be population- and context-dependent, and further long-term randomized trials are needed to clarify the underlying mechanisms [218]. The main characteristics of the key studies are summarized in the table below (Table 2).
5.2. The Mediterranean Diet and the Risk of Alzheimer's Disease: Summary of Epidemiological Evidence
Numerous prospective and cross-sectional studies have demonstrated that greater adherence to the Mediterranean diet is associated with better cognitive health and a reduced risk of developing Alzheimer's disease. Early influential cohort studies, such as those by Gu et al. [23] and Scarmeas et al. [222], showed that higher MeDi scores were linked to a 30–50% lower risk of AD or conversion from MCI to AD, with evidence of a dose–response relationship. Similarly, Morris et al. [22] reported that higher adherence to both the Mediterranean and MIND diets was significantly associated with a lower incidence of AD.
Cross-sectional data support these findings: in the Australian study by Gardener et al. [26], individuals with AD or MCI exhibited significantly lower MeDi scores compared to healthy controls, while higher adherence was related to less decline in MMSE performance over follow-up. In very old adults, Nicoli et al. [223] found that greater adherence to the Mediterranean diet and higher consumption of plant-based foods were associated with lower prevalence and incidence of AD and dementia.
Conversely, some more recent long-term investigations—such as Glans et al. [211]—did not observe significant associations between Mediterranean diet adherence and the risk of AD or overall dementia. These inconsistencies may partly reflect methodological differences in dietary assessment and changes in lifestyle behaviors over time. Overall, current epidemiological evidence suggests that higher adherence to the Mediterranean diet—particularly greater intake of vegetables, fruits, fish, and olive oil—is associated with a significantly lower risk of Alzheimer's disease (Table 3).
5.3. Mediterranean Diet and Parkinson's Disease Risk
Epidemiological evidence increasingly indicates that higher adherence to the Mediterranean diet is associated with a lower risk of Parkinson's disease and a reduced likelihood of developing prodromal PD features. Most cohort and case–control studies report relative risk reductions of 20–50%, with the largest benefits generally observed in European and Mediterranean populations. In Asian populations, risk reductions were somewhat smaller, although the direction of the effect—reduced Parkinson's disease risk—remained consistent. Overall, the strongest associations were observed in Mediterranean, Caucasian, and Latin American cohorts, whereas effects in Asian and African American populations tended to be smaller or less consistent, potentially reflecting differences in baseline dietary patterns, cultural eating habits, and gut microbiome profiles.
In a U.S. cohort of 706 participants, Agarwal et al. [231] found that greater adherence to the MeDi, alongside the MIND diet, was associated with a lower risk of developing parkinsonism (HR = 0.89; 95% CI 0.83–0.96). In a case–control study of 455 individuals, Alcalay et al. [232] reported that high MeDi adherence was linked to a 14% reduction in PD risk (OR = 0.86; 95% CI 0.77–0.97; p = 0.01) and delayed disease onset.
Findings from the Greek HELIAD cohort further support a neuroprotective role of the MeDi. Each one-point increase in MeDi score was associated with a 2% reduction in prodromal PD probability (p < 0.001), and participants in the highest adherence quartile had a ~21% lower risk than those in the lowest quartile [233,234]. Longitudinal analyses showed that higher MeDi adherence reduced the likelihood of developing possible or probable prodromal PD by 60–70% (p-trend = 0.003) and lowered the incidence of PD/dementia with Lewy bodies by approximately 9–10% (HR = 0.906; 95% CI 0.823–0.997).
Consistent findings have been observed in Scandinavian populations. In a study of over 47,000 Swedish women, Yin et al. [235] reported that the highest MeDi adherence was associated with a 46% lower risk of PD (HR = 0.54; 95% CI 0.30–0.98), while each unit increase in MeDi score conferred a 29% lower PD probability among women aged ≥65 years (95% CI 0.57–0.89).
Large U.S. datasets provide further support. Molsberry et al. [236] examined 47,679 participants and found that individuals in the highest aMED quintile had 18–33% lower odds of exhibiting three or more prodromal PD features (OR = 0.82–0.67; p-trend < 0.001). Similarly, Xu et al. [237], using NHANES data, observed that high MeDi adherence was associated with a 22% reduction in PD odds (OR = 0.78; 95% CI 0.65–0.93), whereas adherence to a Western dietary pattern more than doubled PD risk (OR = 2.19; 95% CI 1.16–4.14).
Taken together, these findings consistently support an inverse association between Mediterranean diet adherence and Parkinson's disease risk, as summarized in Table 4.
6. Cognitive Effects of Trans-Resveratrol
Trans-resveratrol has been investigated for its effects on cerebral perfusion, neurovascular function, and cognition in both acute and chronic settings. Acute supplementation studies [242,243,244] consistently demonstrate increased cerebral blood flow and enhanced oxygen extraction in the frontal cortex, accompanied by improved neurovascular coupling. These physiological changes were observed in healthy older adults and individuals with type 2 diabetes. Although acute administration generally did not yield significant improvements on short-term cognitive tests, it reliably supported cerebrovascular responsiveness during cognitive tasks.
Chronic supplementation trials provide stronger evidence for cognitive benefits. Longer-term administration of trans-resveratrol [157,245,246,247,248,249] has been shown to improve memory performance, particularly in domains related to retention and consolidation, while enhancing hippocampal functional connectivity. Several studies also documented increased cerebrovascular responsiveness to cognitive and hypercapnic stimulation, alongside improvements in metabolic parameters such as HbA1c and insulin resistance—factors relevant to neurodegenerative risk. Importantly, most human trials used resveratrol doses in the range of 150–1000 mg/day, which are several hundred-fold higher than the amounts obtainable from a Mediterranean dietary pattern, and therefore the clinical relevance of these findings to dietary intake is limited.
In individuals with mild cognitive impairment or Alzheimer's disease [189,250,251,252,253,254], trans-resveratrol reduced markers of neuroinflammation, activated SIRT1-mediated neuroprotective signaling, and partially preserved hippocampal volume or structure. Cognitive gains in these populations were generally modest, but biological and neuroimaging markers suggest a slowing of neuropathological processes.
Natural dietary sources of resveratrol have also been examined. Grape-based formulations and resveratrol-enriched wine improved attention, working memory, and regional brain metabolism in both younger and older adults [255], supporting the concept that whole-food sources may exert synergistic effects.
Overall, available evidence indicates that trans-resveratrol enhances cerebrovascular function and supports neuroprotective pathways, with the most consistent benefits emerging from chronic supplementation in older adults and individuals at increased risk of cognitive decline. It is important to note that the doses of trans-resveratrol used in clinical supplementation trials (ranging from ~150 mg/day to 1000 mg/day) are substantially higher than the amounts typically obtained from a Mediterranean diet, where average daily intake through natural sources such as red grapes, red wine, and berries is estimated at approximately 1–5 mg/day. Therefore, while supplementation studies provide mechanistic and proof-of-concept evidence for cognitive and cerebrovascular benefits, these effects may not be fully achievable through habitual dietary intake alone. Future research should aim to clarify whether long-term adherence to a polyphenol-rich Mediterranean diet can produce comparable outcomes at physiologically attainable resveratrol levels. Key findings from these studies are summarized in Table 5.
7. Olive Oil-Derived Polyphenols and Their Role in Cognitive Health
7.1. Cognitive Outcomes in MCI and Mild AD Populations Following Olive Oil or Olive Extract Interventions
Several clinical trials have investigated the effects of high-polyphenol extra virgin olive oil and other olive-derived extracts on cognitive performance in adults with MCI and mild AD. Overall, regular consumption of high-polyphenol EVOO or olive extracts has been associated with improvements in cognitive function in these populations. Tsolaki et al. [197] reported that in 50 MCI participants, 12 months of high-polyphenol early harvest EVOO combined with a Mediterranean diet significantly improved MMSE, ADAS-Cog, Digit Span, and Letter Fluency scores compared to moderate-polyphenol EVOO and Mediterranean diet alone (p < 0.05). Dimitriadis et al. [258] found in 43 MCI participants that high-polyphenol EVOO reduced EEG-measured over-excitation, decreased the theta/beta ratio, and enhanced integrated dynamic functional connectivity (p < 0.001).
Kaddoumi et al. [259] conducted a 6-month study with 25 MCI participants and observed that EVOO reduced blood–brain barrier permeability, increased both resting-state and task-based functional connectivity, and improved CDR and behavioral scores. Refined olive oil (ROO) improved CDR scores and task-based activation but did not affect BBB permeability or functional connectivity. Both EVOO and ROO lowered plasma Aβ42/Aβ40 and p-tau/t-tau ratios. Since refined olive oil contains only negligible amounts of oleuropein and other polyphenols, the observed cognitive effects cannot be attributed to oleuropein, and alternative mechanisms—such as the high monounsaturated fatty acid (MUFA) content—are more likely to account for these findings. This distinction should be considered when interpreting the results.
In mild AD populations, olive leaf extract (OLE) and oleuropein + S-acetyl-glutathione supplementation preserved or improved cognitive and functional scores over 6 months [260,261]. Additionally, low-dose EVOO integrated into the Mediterranean diet improved ADAS-Cog scores over 12 months [262]. Collectively, these findings support the cognition-enhancing effects of high-polyphenol EVOO and olive-derived extracts in MCI and mild AD populations (Table 6).
7.2. Olive Oil Polyphenols and Cognitive Function: Evidence from Mediterranean Diet Studies
Among epidemiological and intervention studies examining the effects of the Mediterranean diet on cognitive function, several highlight the role of extra virgin olive oil and olive polyphenols, including oleuropein, in improving memory performance and global cognitive function. In the PREDIMED trial, participants consuming EVOO showed significant improvements in the MMSE and Clock Drawing Test (CDT) compared with the control group [196]. Similarly, Valls-Pedret et al. [218,263] reported that a polyphenol-rich Mediterranean diet, including olive oil, was positively associated with enhanced verbal memory, working memory, and frontal cognitive components.
Cross-sectional studies, such as Anastasiou et al. [219] and Andreu-Reinón et al. [264], have shown that higher Mediterranean diet adherence—particularly with olive oil consumption—is associated with reduced dementia risk and better memory performance. Further evidence from Bajerska et al. [265] and Talhaoui et al. [266] indicates that specific olive oil intake, independent of total diet scores, supports cognitive domains such as global cognition, visual memory, and executive function, highlighting the neuroprotective potential of olive oil and its polyphenols, including oleuropein, in older adults.
It is important to note that refined olive oil contains negligible amounts of oleuropein and other polyphenols; thus, any cognitive improvements observed with ROO are likely mediated by other components, such as monounsaturated fatty acids or minor bioactive compounds, rather than the polyphenols responsible for the effects of high-polyphenol extra virgin olive oil. While the Mediterranean diet naturally provides EVOO and polyphenols, additional supplementation can deliver higher doses of bioactive compounds, potentially enhancing neuroprotective effects, improving bioavailability, or more effectively targeting cognitive pathways.
Overall, current evidence suggests that incorporating olive oil and polyphenol-rich foods into the Mediterranean diet may be critical for preventing Alzheimer's disease and other cognitive impairments, particularly in aging populations (Table 7).
8. Non-Olive Polyphenols and Cognitive Function: Evidence from Flavonoids, Catechins, and Cocoa Flavanols
This review does not provide an exhaustive analysis of trials focusing on general polyphenol supplementation or broader polyphenol subclasses (e.g., Ginkgo biloba, soy isoflavones, anthocyanins, cocoa flavanols, flavonoid extracts, chlorogenic acids, curcuminoids). These areas encompass more than one hundred clinical trials and have been comprehensively reviewed elsewhere. Within the scope of this article, these compounds are briefly summarized to contextualize the wider evidence base linking polyphenol intake to cognitive aging.
Multiple prospective cohort studies suggest that higher dietary intake of flavonoids and other polyphenols is associated with slower age-related cognitive decline. In the SU.VI.MAX cohort, Kesse-Guyot et al. [271] reported that higher intakes of total polyphenols—particularly catechins, theaflavins, and flavonols—were associated with better verbal memory and language performance in middle-aged adults. Similarly, in the Nurses' Health Study, greater midlife flavonoid consumption was linked to a higher likelihood of healthy aging, including preserved cognitive and mental function [272].
These findings are consistent with results from the Framingham Offspring Study, where Shishtar et al. [273] observed a trend toward slower cognitive decline with higher flavanol intake. Data from the Memory and Aging Project further showed that dietary patterns rich in green leafy vegetables and their bioactive components [e.g., lutein, folate, vitamin K] were associated with significantly slower cognitive decline [274]. Collectively, this evidence supports the hypothesis that flavonoid- and polyphenol-rich diets during midlife may confer protection against late-life cognitive deterioration through antioxidant, anti-inflammatory, and neuroprotective mechanisms.
Human observational and interventional studies consistently indicate that flavonoids found in berries and grapes—particularly anthocyanins and flavanols—are associated with beneficial cognitive effects. In the Nurses' Health Study, Devore et al. [275] reported that higher blueberry and strawberry consumption was linked to slower cognitive aging in older women, corresponding to approximately 2–2.5 years of cognitive "youthfulness."
Interventional evidence complements these findings. Krikorian et al. [276] showed that 16 weeks of Concord grape juice supplementation improved memory and increased neural activation in older adults with MCI. In a six-month placebo-controlled trial, Lee et al. [254] found that freeze-dried grape powder (FDGP), rather than isolated grape polyphenols, preserved metabolic integrity in brain regions vulnerable in early Alzheimer's disease. Additionally, long-term data from the Framingham Offspring Study revealed that higher intakes of flavonols, anthocyanins, and flavonoid polymers were associated with significantly lower risk of Alzheimer's disease and related dementias (HR 0.24–0.58) [277]. Together, these results suggest that regular consumption of flavonoid-rich berries and grapes may slow cognitive decline and reduce neurodegenerative risk.
Catechins—major polyphenols in green tea—exhibit well-documented antioxidant, anti-inflammatory, and neuroprotective properties [278,279,280]. Clinical trials support cognitive benefits in midlife and older adulthood. In a double-blind, randomized, placebo-controlled trial, Baba et al. [281] found that 12 weeks of daily supplementation with decaffeinated green tea catechins (336 mg) improved cognitive performance in Japanese adults aged 50–69 years. Participants exhibited reduced error rates after a single dose and faster response times on working memory tasks after 12 weeks.
Consistent results were reported by Ide et al. [282], who observed improvements in overall cognitive performance—particularly attention and memory—in elderly Japanese individuals with MCI. These findings suggest that habitual intake of green tea catechins may confer modest but measurable cognitive benefits, likely mediated by antioxidant and neuroprotective mechanisms.
A growing body of evidence also supports the cognitive benefits of cocoa-derived flavanols, particularly in older adults. In the Cocoa, Cognition and Aging (CoCoA) studies, daily consumption of cocoa flavanols for eight weeks improved attention, executive function, and verbal fluency in older individuals with normal cognition and in those with MCI [283,284]. These improvements were accompanied by reductions in insulin resistance, blood pressure, and oxidative stress, suggesting that vascular and metabolic pathways may mediate the observed cognitive effects.
A retrospective clinical study in MCI patients found that higher cocoa polyphenol intake was associated with slower progression of cognitive decline [285]. Long-term cohort data also show that regular chocolate consumption is inversely correlated with cognitive decline risk, independently of age, education, and cardiovascular factors [286]. Together, these findings indicate that habitual cocoa flavanol consumption may help preserve cognitive function and support healthy brain aging.
9. Discussion and Conclusions
This review integrates epidemiological, clinical, and mechanistic evidence linking adherence to the Mediterranean diet with healthier cognitive aging and a reduced risk of neurodegenerative diseases. Prospective cohort studies consistently show that individuals who closely follow the Mediterranean diet experience slower cognitive decline and lower incidence of Alzheimer's disease, Parkinson's disease, and related dementias. Although population-specific variability exists, the overall evidence supports a protective association. Clinical interventions, particularly those incorporating high-polyphenol extra virgin olive oil, have demonstrated improvements in memory, executive function, cerebrovascular responsiveness, and disease-relevant biomarkers.
Mechanistic data provide a coherent biological rationale for these observations. Mediterranean diet components modulate multiple pathways central to neurodegenerative processes, including oxidative stress, chronic inflammation, mitochondrial dysfunction, cerebrovascular impairment, and gut–brain axis regulation. Polyphenols—especially resveratrol, oleuropein, and hydroxytyrosol—appear particularly relevant due to their roles in modulating amyloid and tau pathology, activating SIRT1, supporting mitochondrial and endothelial integrity, and regulating neuroinflammatory signaling.
It should be noted that much of the mechanistic evidence derives from in vitro studies, animal models, or metabolic biomarkers, whereas human, long-term neural outcomes (cognition, neurodegeneration, protein aggregation) remain limited. Daily intake of resveratrol and oleuropein from a typical Mediterranean diet is extremely low (~1 mg/day), suggesting that these compounds alone are unlikely to account for the observed cognitive benefits. Therefore, mechanistic and intervention studies must clearly specify the model system (cellular, animal, or human) and compare administered doses with achievable dietary intake levels. Moreover, extra virgin olive oil contains a complex mixture of polyphenols, and cognitive benefits likely reflect synergistic effects between polyphenols and other bioactive components, such as monounsaturated fatty acids. Overall, the cognitive benefits of the Mediterranean diet are probably not attributable to a single polyphenol, but rather to the combined action of multiple dietary components.
The clinical relevance of the Mediterranean diet extends beyond prevention. Its multidimensional biological effects suggest potential as a complementary therapeutic strategy for individuals with mild cognitive impairment or early-stage neurodegenerative disease. Polyphenols may also serve as biomarkers of dietary exposure and biological effect, and targeted supplementation could be considered for individuals with insufficient habitual intake. Responses to dietary and polyphenol-based interventions are likely individual-specific, influenced by genetics, comorbidities, physical activity, smoking, sleep patterns, and regional dietary habits. Collectively, the evidence supports the Mediterranean diet as a biologically plausible, feasible approach to promote cognitive health, with mechanistic and clinical data highlighting the importance of the synergistic action of multiple dietary components rather than any single polyphenol.
Interpretation of the literature must also take into account several limitations. Considerable variability exists in the scoring systems used to assess Mediterranean diet adherence, as well as in the dietary assessment tools themselves, which complicates the comparison of results across studies. Many cohort studies rely on self-reported dietary intake, which introduces recall bias. Interindividual differences in polyphenol absorption, metabolism, and bioavailability introduce further heterogeneity, as do differences in gut microbiome composition and lifestyle habits. Randomized controlled trials remain relatively few, often involve modest sample sizes and short intervention periods, and employ diverse formulations of polyphenol-rich foods or supplements. Importantly, the bioavailability of resveratrol in dietary sources is low and highly variable, and intervention doses used in mechanistic studies often exceed what can be achieved through habitual dietary intake, highlighting the need for careful interpretation of translatability. Furthermore, the studies summarized in the tables exhibit considerable heterogeneity, not only in dietary assessment methods but also due to geographical and cultural differences, which complicates direct comparison and synthesis of results. These limitations underscore the need for additional mechanistic and translational research in humans.
Future studies should aim to include larger, multicenter clinical trials with harmonized definitions of MedDiet adherence and standardized intervention protocols. The incorporation of biomarker-based endpoints—such as measures of amyloid and tau pathology, neuroinflammation, vascular function, and microbiome composition—will be crucial to clarifying causal pathways and strengthening the clinical relevance of findings. Integrating neuroimaging, metabolomics, and vascular assessments will help elucidate how specific components of the MedDiet contribute to neuroprotection and which individuals are most likely to benefit from dietary modification or targeted polyphenol supplementation. Such work is essential to advance the development of personalized nutritional strategies for neurodegenerative disease prevention and management.
In conclusion, although important gaps in our understanding remain, the collective evidence suggests that the Mediterranean diet is a promising, feasible, and biologically plausible approach to support cognitive health and reduce the burden of neurodegenerative diseases. Polyphenols—particularly those derived from extra virgin olive oil and grapes—likely contribute to these benefits through their combined antioxidant, anti-inflammatory, mitochondrial, and anti-amyloid actions, but the overall protective effect of the MedDiet is likely due to the synergistic interaction of multiple dietary components rather than the effect of any single polyphenol. Continued research focusing on biomarker-based outcomes, dose–response relationships, and precision nutrition strategies will be essential to translate these insights into targeted dietary recommendations and clinically meaningful interventions for individuals at risk of cognitive decline and neurodegeneration.