4.1. Impact of Mediterranean Diet on ADRD Progression

The Mediterranean diet (MedD), created by an American couple in the 1960s, is inspired by the eating habits of people in Greece, Southern Italy, and Spain in the 1940s and 1950s [45]. These habits involve a high consumption of olive oil, unrefined cereals, fruits, and vegetables; a moderate to high consumption of fish; a moderate consumption of dairy products (mostly cheese and yogurt); moderate wine consumption; and a low consumption of red meat products [12]. The MedD consists of nutrient-dense foods that have been recognized as beneficial for overall health and healthy brain aging [9]. It has been associated with a lower risk of conversion from mild cognitive impairment to dementia [46,47,48,49], a reduction in dementia incidence [46,50,51,52,53,54,55,56], the maintenance of brain health [20,57], a lower risk of cognitive decline [41,58,59,60,61,62,63], and better cognition [64,65]. However, some inconsistencies are observed among studies regarding the benefits of the MedD on cognition and cognitive aging, particularly with regard to ADRD. Some studies did not find significant associations between the MedD and a decrease in ADRD incidence and/or conversion from mild cognitive impairment to dementia, which may be attributed to recruiting participants from outside the Mediterranean area [21,56,66,67,68,69,70,71,72,73,74]. There is evidence that the benefits of the MedD may be more prominent among individuals who have adhered to the MedD throughout their lives and reside in the Mediterranean region compared to those who adopt this dietary pattern later in life [75]. Another factor contributing to the contradictory results is the variation in the qualitative and quantitative food components prescribed in different studies. For example, some studies grouped all polyunsaturated fatty acids together, while others focused solely on olive oil. Additionally, the quantities of different components of the diet vary among studies. A randomized study, for instance, examined the impact of the MedD supplemented with olive oil or nuts and identified a significant improvement in global cognition and/or specific cognitive domains among a Spanish population with cardiovascular risk factors over a period of 6.5 years [76]. Furthermore, there is considerable variation in the scoring systems used across different studies, which can lead to disparities in estimating nutrient intake and compliance with the MedD [77]. It is important to consider potential sources of discrepancies in research findings, which may stem from differences in the studied populations, including factors such as gender (males or females only), the presence of obesity or cardiovascular diseases, and the duration of the studies. The timing of dietary adherence, whether it occurs during midlife or late life, also needs careful consideration. Table 1 provides a compilation of observational, longitudinal, and intervention studies conducted in the past 10 years examining the MedD and its association with ADRD risk factors.

In addition to cognitive outcomes associated with ADRD risk, recent research has examined the effect of the MedD on AD biomarkers, specifically β-amyloid and phosphorylated tau tangles. In a systematic review and meta-analysis conducted by Hill et al. [78], it was concluded that adherence to a Mediterranean-style dietary pattern was associated with a reduction in AD biomarkers (β-amyloid and tau tangle) and subsequent pathology. Specifically, in the latest published study by Agarwal et al. [79], which involved autopsied older adults, higher scores of adherence to the MedD were significantly associated with lower global AD pathology (p = 0.039). Even after adjusting the models for other covariates, such as physical activity, smoking, and vascular disease burden, the association remained significant (p = 0.027). When excluding the dietary assessments from the last year of life of the participants to account for events that might have altered their diet, greater overall adherence to the MedD for almost a decade remained significantly associated with reduced global AD pathology and β-amyloid load.

Furthermore, the MedD has shown potential in reducing the incidence of ADRD through its beneficial effects on blood pressure [80], mitochondrial structure and function [81], the preservation of white matter microstructure [82,83], the induction of cerebral blood flow [81], cortical thickness [84], and the accumulation of white matter hyperintensities [85]. The MedD can also act through a variety of mechanisms, including anti-inflammatory, antioxidant, and lipid-lowering actions [86,87], as well as its favorable impact on cardiovascular risk factors [87,88,89]. MedD has also been associated with higher total brain volume and cortical thickness and lower white matter hyperintensities [84,90,91,92,93]. All these factors can contribute to reducing ADRD (Figure 2).

It should be noted that adherence to the MedD may come with higher financial costs compared to other diets, as reported in studies conducted in the UK and Spain that highlighted this aspect [94,95]. Therefore, individuals with higher incomes have a higher likelihood of adhering to the MedD [96]. Future studies focusing on the MedD should consider the participants’ socioeconomic status as a covariate for dietary analysis [75], as well as other lifestyle factors, such as social contact and physical activity [97,98].

Figure 2

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Hypothesized direct and indirect impacts of dietary patterns on ADRD [12,46,47,48,49,50,51,52,53,54,55,56,85,86,93,99,100,101,102,103]. BDNF: Brain-Derived Neurotrophic Factor; NMDR: N-methyl-D-aspartate receptor; CNS: central neural system; SCFAs: short-chain fatty acids; HPA: hypothalamic–pituitary–adrenal; ↑ higher; ↓ lower.

4.2. Impact of DASH Diet on ADRD Progression

The Dietary Approaches to Stop Hypertension (DASH) diet is a dietary pattern that aims at preventing and treating hypertension and improving cardiovascular health [110]. The DASH diet shares several similarities with the MedD, as both encourage a high intake of plant-based foods. However, the DASH diet also emphasizes the low consumption and/or limitation of dietary sodium, sweetened beverages, and red meats, and it does not recommend alcohol [12]. Similar to the MedD, the DASH diet has been shown to prevent several cardiovascular risk factors, including high blood pressure and LDL cholesterol, which are associated with the development of dementia and particularly ADRD. Additionally, the DASH diet can modulate oxidative stress, inflammation, and insulin resistance, which are involved in the pathological process of ADRD (Figure 2) [111]. Long-term adherence to the DASH diet has been associated with better cognitive function. For example, this association was found in older American women participating in a six-year follow-up study from the Nurses’ Health study [112], as well as in an observational study spanning 11 years involving older adult men and women in the Cache County Memory Study [104], and in participants of the Memory and Aging Project over 4.1 years, who exhibited slower rates of cognitive decline [58]. However, a cross-sectional study focusing on sedentary adults with cognitive impairment and cardiovascular disease risks reported mixed results regarding cognitive functions. While high adherence to the DASH diet was associated with better verbal memory, it had no effect on executive function, processing speed, or visual memory [102]. Another randomized trial concluded that combining the DASH diet with weight management significantly improved executive function and memory/learning (p = 0.008). When the DASH diet was implemented alone, it showed an improvement in psychomotor speed (p = 0.036) for hypertensive overweight adults in the U.S. after a 4-month intervention [103]. In the same study, when combining the DASH diet intervention with weight management, greater improvements were observed in executive function, memory, learning (p = 0.008), and psychomotor speed (p = 0.023).

Discrepancies have been reported, as other studies have not found a significant association between the DASH diet and cognition. For instance, a prospective longitudinal study among older women in the Women’s Health Initiative Memory Study by Haring et al. [73] concluded that the DASH diet had no significant association with cognitive decline, nor did a high DASH score have an impact on cognitive decline in older community participants (both men and women) in other longitudinal studies [41,113,114]. Another six-month randomized controlled trial with sedentary men and women concluded that the DASH diet alone did not improve cognitive impairment (p = 0.059), but when combined with aerobic exercise, a considerable improvement in executive function (p = 0.012) was observed [115]. These results suggest that the DASH diet, when combined with other non-dietary interventions, possibly synergistically, provides a neuroprotective effect. Table 2 summarizes the different clinical trials investigating the relationship between the DASH diet and ADRD and cognition in the last 10 years. The observed discrepancies in Table 2 may be attributed to differences in study design (RCT vs. observational or cross-sectional), the number and variety of participants (e.g., men only, specific age group, obese or lean individuals), the scoring systems used to define adherence to the DASH diet, and the food products considered in each study. Overall, while the existing evidence hints that the DASH diet might be beneficial for cognitive functioning, further research is needed to validate these findings and demonstrate the benefits of DASH for ADRD progression and risk.

4.3. Impact of MIND Diet on ADRD Progression

The MIND diet, which stands for Mediterranean-DASH Intervention for Neurogenerative Delay, combines elements from both the Mediterranean and DASH diets, with a specific focus on dietary components with neuroprotective effects [12]. Unlike the Mediterranean diet, the MIND diet emphasizes the consumption of berries and green leafy vegetables rather than a high intake of fruits. Numerous observational studies and clinical trials have examined the impact of the MIND diet on ADRD progression (Table 3), and all of these studies suggest a positive association with better cognition [20,41,100,116,117,118,119], lower risks of cognitive impairment [74], and a reduced risk of developing AD [100]. An observational study conducted by Morris et al. [100] over an average of 4.7 years highlighted that high adherence to the MIND diet was associated with less cognitive decline compared to low adherence (p < 0.0001), suggesting that the MIND diet may slow the rate of cognitive decline. Another cross-sectional study involving older U.S. citizens found that higher adherence to the MIND diet was associated with improved cognitive function in a dose–response manner (p < 0.001) [65]. Long-term adherence to the MIND diet was associated with moderately improved verbal memory in later life over a 12.9-year follow-up [120], and a longitudinal study with a 12-year follow-up concluded that the MIND diet reduced the risk of cognitive decline by 53% [74]. Additionally, a study on older adults with a 6-year follow-up on MIND diet adherence showed that a one-point increase in the MIND diet score was associated with a 14% reduction in the risk of subjective memory complaints [121]. Furthermore, a study on older adults highlighted a strong and significant association between MIND diet adherence and better cognitive functioning, even among those diagnosed with AD before or after death [122]. A systematic search conducted by Chu et al. [12] concluded that higher adherence to the MIND diet may be associated with a lower incidence of cognitive impairment and AD, while the MedD appears to provide greater neuroprotection against ADRD. Huang et al. [123] attempted to establish a Chinese version of the MIND diet that aligned with Chinese dietary characteristics and culture while also being more affordable. Moderate and high adherence to the developed Chinese MIND diet were both associated with lower odds of cognitive impairment and IADL disability (0.81 and 0.6, respectively), even after adjusting for covariates. In a recent study by Agarwal et al. [79], higher MIND diet scores were negatively correlated with lower global AD pathology (p = 0.047), and this association remained significant even after adjusting for other covariates (p = 0.047). Participants who had a one-unit higher MIND diet score showed amyloid loads similar to those of individuals who were four years younger [79]. This effect persisted even after adjusting for other lifestyle factors and the burden of vascular disease. A randomized controlled trial conducted over 3 months with a MIND diet intervention for postmenopausal women demonstrated a significant improvement in working memory and verbal recognition [124]. However, combining the MIND diet with different lifestyle components, particularly physical activity, may be more effective in slowing ADRD progression when diagnosed early, as indicated by a cross-sectional study involving both physical activity and the MIND diet in an older adult population [125]. Overall, the current evidence indicates that the MIND diet may be associated with a reduced risk of ADRD and slowed ADRD progression.

Table 3

A summary of clinical studies examining MIND diet impact on ADRD.

Study Design	Country	Population	Follow-Up	Exposure	Outcome	Results	Covariates	Reference
Longitudinal	US	Older adults n = 923 (±24% men) Age: 58–98 years	4.5 years	144-item SFFQ, A-MeDi, A-DASH, and MIND scores	AD (based on NINCDS-ADRDA criteria)	Middle and high tertiles of MIND diet score significantly associated with lower risk of AD.	Age, gender, education, presence of APOE ε4 allele, participation in cognitively stimulating activities, physical activity, total energy intake, and cardiovascular conditions.	[100]
Longitudinal	US	Older adults n = 960 (25% men) Age: 81.4 years	4.7 years	144-item SFFQ, MIND diet score	Global cognition, episodic memory, semantic memory, visuospatial ability, perceptual speed, and working memory	MIND diet score significantly associated with slower in global cognition; episodic memory; semantic memory; visuospatial ability; perceptual speed; and working memory. Higher tertile of MIND diet score significantly associated with slower in global cognitive score.	Age, gender, education, participation in cognitive activities, smoking history, physical activity hours per week, total energy intake, presence of APOE ε4 allele, time, history of stroke, myocardial infarction, diabetes, hypertension, and interaction terms between each covariate and time).	[100]
Longitudinal	Sweden	Older-adult community residents n = 2223 (39% men) Age: 69.5 years	6 years	98-item SFFQ, A-MeDi, A-DASH, and MIND scores, dietary components	Global cognition (MMSE)	Higher MIND score significantly associated with less cognitive decline and lower risk of MMSE score ≤ 24.	Total caloric intake, age, gender, education, civil status, physical activity, smoking, BMI, vitamin/mineral supplement intake, vascular disorders, diabetes, cancer, depression, presence of APOE ε4 allele, and dietary components other than main exposure in each model.	[41]
Longitudinal	US	Older women n = 16,058 (0% men) Age: 74.3 years	12.9 years	116-item FFQ, MIND score	Global cognition (TICS and composite score of TICS, EBMT) and verbal memory (immediate and delayed recalls).	Higher adherence to MIND diet not significantly associated with less in global cognition, verbal memory, or TICS score.	Age, education, physical activity, caloric intake, alcohol intake, smoking status, multivitamin use, BMI, depression, and history of hypertension, hypercholesterolemia, myocardial infarction, and diabetes mellitus.	[120]
Longitudinal	Australia	Older Australian adults n = 1220 (50% men) Age: 60–64 years	12 years	CSIRO-FFQ, MeDi, A-MeDi, and MIND scores, dietary components	Cognitive impairment: MCI/dementia	Higher tertile of MIND score significantly associated with a lower risk of cognitive impairment.	Energy intake, age, gender, presence of APOE ε4 allele, education, mental activity, physical activity, smoking status, depression, diabetes, BMI, hypertension, heart disease, and stroke.	[74]
Longitudinal	US	Older adults with clinical history of stroke n = 106 (29 M 77 F) Age: 82.8 ± 7.1 years	5.9 years	144-item FFQ, neuropsychologic battery of tests/global cognitive decline: episodic memory, semantic memory, working memory, perceptual orientation, perceptual speed	Determination of whether the MIND diet is effective in preventing cognitive decline after stroke	Higher tertile compared with lowest one of MIND diet scores had slower rate of global cognitive and slower in semantic memory and perceptual speed. In continuous models, MIND diet associated with slower in cognitive function for global cognition and semantic memory.	Age, gender, education, total energy intake, presence of APOE ε4 allele, smoking, participation in cognitive and physical activities, depressive symptoms, BMI, chronic diseases.	[116]
Longitudinal	US	Population WRAP study n = 828 (268 M 560 F) Age: 57.7 ± 6.4 years, free of dementia and MCI at baseline	6.3 years	15-item questionnaire, neuropsychological battery of tests/ multidomain cognitive composite: immediate memory, delayed memory, executive function	Effect of MIND diet on multidomain cognitive composite and immediate/delayed memory and executive function composites	Higher MIND diet scores associated with slower in executive function. MIND diet not associated with PACC4, immediate memory, or delayed memory.	Age, gender, presence of APOE ε4 allele, cognitive activity, physical activity, education.	[117]
Longitudinal	Germany	Older adults from DELCODE study n= 389 (187 M 202 F), free of dementia Age: 69.4 ± 5.6 years Subjective Cognitive Decline group (SCD): n = 146 MCI group: n = 60 First-degree relatives of AD dementia patients: n = 35 Healthy controls: n = 148	NS	148-item FFQ neuropsychological battery of tests and MMSE tool/cognitive function: memory, language (verbal fluency), executive functioning, working memory, visuospatial functioning	Associations between dietary patterns and cognitive functioning in older adults free of dementia	Higher MIND diet score associated with better memory in total subjects and language functions in cognitively normal subjects. MIND diet not associated with executive functioning, working memory, or visuospatial functioning.	Age, gender, education, BMI, physical activity, smoking, total daily energy intake, presence of APOE ε4 allele.	[126]
Longitudinal	US	Decedent participants from Rush Memory and Aging Project (MAP) n = 569 (70% F), age at death 91 years	NS	Dietary data, cognitive testing proximate to death, and complete autopsy data at the time of the analyses	Examination of whether the association of MIND diet with cognition is independent of common brain pathologies	Higher MIND diet score associated with better global cognitive functioning proximate to death, even after adjustment for AD and other brain pathologies. MIND diet–cognition relationship remained significant when analysis restricted to individuals without MCI at baseline or postmortem diagnosed with AD.	Age at death, gender, years of education, presence of APOE ε4 allele, cognitive activities, and total energy intake.	[121]
Cross-sectional	US	Community-dwelling adults n = 5907 (40% men) Age: 67.8 years	NS	163-item SFFQ, A-MeDi score, MIND diet score	Cognitive performance: immediate and delayed recall, backward counting, and serial seven subtraction	Higher MIND diet scores associated with slower in executive function. MIND diet not associated with PACC4, immediate memory, or delayed memory.	Gender, age, race, low education attainment, current smoking, obesity, total wealth, hypertension, diabetes mellitus, physical inactivity, depression, and total energy intake.	[65]
Cross-sectional	Brazil	Senior participants with different cognition Control: n = 36 (7 M 29 F) Age ≥ 75 years 12% MCI: n = 30 (9 M 21 F) Age ≥ 75 years 50% AD: n = 30 (11 M 19 F) Age ≥ 75 years 63.3%	NS	98-item FFQ, neuropsychiatric battery of tests and MMSE tool/ cognitive performance: naming, incidental memory, immediate memory, learning, delayed recall and recognition	Impact of MIND diet adherence on cognitive performance for different cognitive profiles seniors	Moderate adherence to MIND diet associated with higher MMSE scores. High adherence to MIND diet associated with learning score in healthy older adults but not in MCI or AD. No association between the other cognitive variables and the MIND score.	Age, education, income, marital status, BMI, chronic diseases, having undergone nutritional care, motor or sensory impairments.	[127]
Cross-sectional	China	Older adults from the Chinese Longitudinal Healthy Longevity Study n = 11,245 (45.3% M) Age: 84.06 ± 11.46 years	2 to 3 years	12-items FFQ, Chinese MIND (cMIND)diet score	Cognitive impairment and IADL disability	Moderate and high adherence to cMIND diet associated with lower likelihood of cognitive impairment (higher MMSE score) and IADL disability, even after adjusting for covariates. Higher cMIND diet score associated with better cognitive function and IADL.	Age, gender, residence, education, BMI, diabetes, hearing impairment, hypertension, depression, smoking, drinking, exercise, and social engagement.	[123]
Cross-sectional	US	Data from University of Michigan Health and Retirement Study n = 3463 Age: 68.0 ± 10.0 years	NS	163-item FFQ, MIND diet scores, episodic memory (im- mediate and delayed recall), working memory, attention/processing speed	Association of combination of high-intensity physical activity (PA) and MIND diet with better cognition compared with PA or MIND diet alone or neither	MIND diet alone associated with better global cognition and lower likelihood of cognitive decline. Combining PA and MIND diet predicted better global cognition and lower likelihood of cognitive decline, but did not predict lower odds of cognitive decline compared to PA alone.	Age, gender, race, education, annual income, smoking history, hypertension, diabetes mellitus, depression, and obesity.	[125]
Randomized controlled trial	Iran	Healthy obese women (MMSE = 24) n = 37 MIND group: n = 22 Age 48.95 ± 1.07 years Control group: n = 15 Age 48.86 ± 1.56 years	3 months	168-item FFQ and 3-day food recall, neuropsychological test battery and MMSE tool/verbal short memory, working memory, attention and visual scanning, verbal recognition memory, executive function and task switching, ability to inhibit cognitive interference	Impact of 3 months MIND diet on body composition and cognition	MIND group compared with control had improved working memory, verbal recognition memory, and attention. in the surface area of inferior frontal gyrus in MIND diet group.	Pregnancy, metabolic complications, severe untreated medical, neurological, psychiatric diseases, or gastrointestinal problems.	[124]
Prospective cohort	Spain	Older adults from “Seguimiento Universidad de Navarra” n= 806 (562 M 244 F) without cognitive impairment at baseline Age: 61 ± 6 years	6 ± 3 years	136-item FFQ, telephone-based interview of MMSE/Spanish TICS (orientation, memory, attention/calculation, and language)	Compare association of dietary patterns with cognitive function	Higher adherence to MIND diet associated with upward 6-year changes in Spanish TICS scores. Each 1-point in the MIND score Spanish TICS score by 0.27 points. In adjusted linear mixed model, MIND diet score associated with 0.038 rate of change in STICS scores over 5.6 years.	Age, gender, presence of APOE ε4 allele, smoking, education, total energy intake, physical activity, BMI, alcohol intake, depression, chronic diseases, high cholesterol, low HDL cholesterol.	[128]
Prospective cohort	France	Older Adults in NutriNet-Santé n = 6011 (2384 M 3627 F) without SMC at enrollment	6 years	FFQ, SMC measured with French version of the validated self-administered cognitive difficulties scale	Impact of MIND diet adherence on SMC	MIND diet score not significantly associated with SMC in adults aged 60–69 years. Adherence to MIND diet for >70 years without depressive symptoms associated with SMC. One-point increase in MIND diet score associated with 14% in SMC risk.	Age, gender, marital status, education, occupation, smoking, income, BMI, physical activity, depressive symptoms, chronic diseases, energy intake.	[121]
Prospective cohort	US	Older population of Framingham Heart Study n = 2092 (956 M 1036 F) Age: 61 ± 9 years	6.6 ± 1.1 years	FFQ, neuropsychological testing, and brain MRI scans (n = 1904).	Association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs), or brain atrophy in the community-based Framingham Heart Study	Higher MIND diet scores associated with better global cognitive function, verbal memory, visual memory, processing speed, and verbal comprehension/reasoning and with larger total brain volume following adjustments. Higher MIND diet scores not associated with other brain MRI measures or cognitive decline.	Age, gender, presence of APOE ε4 allele, total energy intake, education, the time interval between completion of the FFQ and the measurement of the neuropsychological and MRI outcomes, BMI, physical activity, smoking status, cardiometabolic factors, and high level of depressive symptoms.	[117]
Cross-sectional and longitudinal	US	Adults from Boston Puerto Rican Health Study n= 1502 (378 M 1124 F) Age: 45–75 years at baseline	8 years	FFQ over 5-year follow-ups, neuropsychological tests, MMSE	Association between long-term adherence to MIND diet and cognitive function in Puerto Rican adults	In cross-sectional and longitudinal analyses, the highest compared to lowest MIND quintile associated with better cognition function, but not with cognitive trajectory over 8 years.	Income-to-poverty ratio, education level, and job complexity score.	[118]
Longitudinal study and meta-analysis	China	Participants from the China Health and Nutrition Survey (CHNS) n = 4066 participants Meta-analysis: results from the longitudinal study and 7 other MIND diet and cognitive effect studies n = 26,103	3-day 24 h dietary recall, battery of cognitive tests, immediate and delayed recall memory, attention, and calculation abilities	Median 3 years	Relationship between MIND diet and cognitive function and its decline among middle-aged and older adults	Higher MIND diet scores were significantly associated with better global cognitive function. Each increment of 3 points in MIND diet score has adjusted difference in global cognitive function z-score approximately equivalent to being one year younger in age. In the meta-analysis of 26,103 participants, 1 standardized deviation MIND score increment associated with 0.042-unit higher global cognitive function z-score and 0.014-unit slower annual cognitive decline.	Age, gender, education, annual household income per capita, residence, region, smoking, alcohol drinking, BMI, total energy intake, physical activity, history of chronic diseases included self-reported hypertension, diabetes, and myocardial infarction diagnosis, and use of antihypertensive and anti-diabetic medications.	[119]

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Adapted from [20] and updated. AD: Alzheimer’s disease; APOE: apolipoprotein E; BMI: body mass index; CSIRO-FFQ: Commonwealth Scientific and Industrial Research Organization semi-quantitative food frequency questionnaire; EBMT: East Boston Memory Test; FFQ: Food Frequency Questionnaire; HDL: High-Density Lipoprotein; IADL: Instrumental Activities of Daily Living; MCI: mild cognitive impairment; MMSE: Mini-Mental State Examination; MRI: Magnetic Resonance Imaging; PA: high-intensity physical activity; PACC4: Preclinical Alzheimer’s Cognitive Composite 4; SBI: silent brain infarcts; SFFQ: semi-quantitative food frequency questionnaire; SMC: subjective memory complaints; TICS: Telephone Interview for Cognitive Status; : decline; : increase.

4.4. Impact of Ketogenic Diet on ADRD Progression

The ketogenic diet is characterized by high fat and low carbohydrate intake, which promotes ketone production for energy [12]. This diet has been successfully used to treat patients with refractory epilepsy [129], and growing evidence indicates that it may have benefits for cognitive functioning. In a recent case study conducted by Morrill and Gibas [130], the ketogenic diet was found to increase cognitive assessment scores in ApoE4-positive patients with mild AD. Chu et al. [12] extensively reviewed human studies linking the ketogenic diet to cognitive impairment and ADRD development. Out of the 15 identified studies, 14 indicated a significant improvement in cognitive function when ketogenic diets or ketone supplements were administrated to patients with mild cognitive impairment, mild-to-moderate AD, or AD. Grammatikopoulou et al. [131] identified 10 randomized controlled trials that focused on the impact of ketogenic therapies on improving cognitive function and delaying AD progression. The beneficial effects of the ketogenic diet were observed both after acute consumption and with long-term adherence, particularly in participants with mild cognitive impairment. One characteristic of the ketogenic diet is its level of restrictiveness compared to other ‘healthy’ diets, such as the Mediterranean, MIND, and DASH diets [12]. Individuals adhering to the ketogenic diet often experience adverse gastrointestinal events and hypoglycemic episodes during the initial phase [132]. Additionally, long-term compliance with the ketogenic diet presents challenges. For instance, for older adults with mild cognitive impairment or established ADRD health conditions, a drastic shift toward a high-fat dietary pattern can have detrimental effects on their cardiovascular health [12,130]. The potential benefits identified in current studies suggest that more research is needed to evaluate the long-term benefits and side effects, as well as research addressing adherence to this more restrictive eating pattern. It is important to note that, to the best of our knowledge, there are no large-scale RCTs examining ketogenic diet and cognition, so more research is needed in this area.

4.5. Impact of Modified Mediterranean-Ketogenic Diet on ADRD Progression

To meet the dietary requirements of the late-middle-aged population and mitigate the potential negative consequences of long-term adherence to the ketogenic diet, Taylor et al. [133] proposed making the ketogenic diet nutritionally dense. This led to the development of a new diet called the modified Mediterranean-ketogenic diet (MMKD), which combines key elements of the Mediterranean and ketogenic diets. The target macronutrient composition of the MMKD is approximately 5–10% carbohydrate, 60–65% fat, and 30% protein as a percentage of total caloric intake [134]. The diet encourages the consumption of protein sources low in saturated fats, such as fish and lean meats, along with healthy fats, with a particular emphasis on extra virgin olive oil as the main source of fats. It also promotes the intake of fruits, vegetables, and whole grains within certain limits and allows for the consumption of one glass of wine per day [135]. Since the MMKD is relatively new, a few studies have investigated its relationship with AD progression (Table 4). In a pilot study, Nagpal et al. [136] highlighted that the MMKD can modulate the gut microbiome and metabolites, which are associated with improved AD biomarkers in the cerebrospinal fluid. However, they reported an increase in cerebrospinal fluid Aβ42 but a decrease in tau at the end of the 6-week intervention. Similar observations were made in a randomized controlled trial conducted by Neth et al. [135]. A 12-week intervention with MMKD resulted in improved cognitive function and everyday functioning [137]. In a crossover trial investigating the impact of MMKD, a decrease in adiposity was found to be correlated with a similar decrease in cerebrospinal fluid biomarkers [134]. The latest review conducted by Wang et al. [138] addresses different diet patterns and individual food product intake and their respective impacts on ADRD. However, conducting more studies with a large number of participants will help uncover the hidden mechanisms and better understand the impacts of MMKD on individuals with mild cognitive impairment or ADRD.

Table 4

A summary of clinical studies examining modified Mediterranean-ketogenic diet impact on ADRD.

Study Design	Country	Population	Follow-Up	Exposure	Outcome	Results	Covariates	Reference
Randomized, double-blind, crossover single-center pilot study	US	n = 17 Age: 64.6 ± 6.4 years Participants with MCI n = 11 Participants with normal cognitive function n = 6	6-week interventions: MMKD and AHA diet separated by 6-week washout	Gut microbiome, fecal short-chain fatty acids, markers of AD in cerebrospinal fluid	Change in gut microbial signature, fecal short-chain fatty acids, and AD biomarkers after each diet intervention.	MMKD associated with improved metabolic indices and AD biomarkers in CSF profile.	NS	[136]
Randomized crossover trial	US	Participants with MCI n= 9 (3 M 6 F) Age: 63.4 ± 4.0 years Participants with SMC n= 11 (2 M 9 F) Age: 64.9 ± 7.9 years	MMKD diet and AHA diet for 6 weeks followed by 6-week washout	Immediate and delayed memory, general cognition, plasma biomarkers, CSF biomarkers, and MRI	Compare effects of MMKD and AHA diet on AD biomarkers in CSF, neuroimaging measures, peripheral metabolism, and cognition.	MMKD associated with CSF Ab42 and t-tau.	Age, presence of APOE ε4 allele, and order of diet intervention.	[135]
Randomized controlled trial	New Zealand	Participants with diagnosed AD n= 26 (16 M 10 F) Age: 69.8 ± 6.0 years	12-week intervention and 10-week washout, low-fat diet and MMKD	FFQ, cognition by ACE-III, daily function by ADCS-ADL, quality of life by QOL-AD	Change in cognition, daily function, or quality of life in AD patients after 12 weeks of MMKD.	Improvement in cognitive function, everyday functioning, and quality of life for MMKD group participants compared with the low-fat diet ones.	NS	[137]
Crossover trial	US	Participants with MCI n = 9 (3 M 6 F) Age: 63.4 ± 4.0 Participants with SMC n = 11 (2 M 9 F) Age: 64.9 ± 7.89 years	MMKD and AHA diet for 6 weeks with a 6-week washout period	Dual-energy X-ray absorptiometry for adiposity and CSF biomarkers	Effects of MMKD compared to AHA diet on body weight, body composition, and body fat distribution and their association with AD biomarkers in CSF.	in body fat on the MMKD related to changes in Aβ biomarkers.	Age and diet order	[134]

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ACE-III: Addenbrookes Cognitive Examination-III; ADCS-ADL: Alzheimer’s Disease Cooperative Study—Activities of Daily Living; AD: Alzheimer’s disease; AHA: American Heart Association; APOE: apolipoprotein E; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MMKD: modified Mediterranean-ketogenic diet; MRI: Magnetic Resonance Imaging; PET: Positron Emission Tomography; SCFA: short-chain fatty acids; SMC: subjective memory complaints; QOL-AD: Quality of Life in Alzheimer’s Disease questionnaire; : decline; : increase.

4.6. Impact of Vegetarian Diet on ADRD Progression

A vegetarian diet is not just a plant-based diet that restricts animal products but is also characterized by a low consumption of saturated fat and a high intake of vegetables, fruits, whole grains, legumes, nuts and seeds, dairy products, and/or eggs [139,140]. The extent to which this diet includes discretionary foods, such as sugar-sweetened beverages, desserts, and potato chips, determines its classification as a ‘healthy’ plant-based food pattern [141]. The vegetarian diet has been associated with a lower risk of several chronic diseases and may have the potential to reduce the risk of cardiometabolic and neurodegenerative diseases (Figure 2) [142]. Despite the increasing number of individuals globally adopting a vegetarian diet, only a few studies have specifically investigated the relationship between this dietary pattern and cognitive impairment, particularly ADRD (Table 5). The Adventist Health Study-2 included older adults who followed a vegetarian or non-vegetarian diet. This cohort demonstrated that vegetarians had higher adherence to their dietary patterns constantly over decades, which was associated with better memory and language abilities [143]. Liu et al. [141] assessed the difference in cognition among different races and dietary patterns. They found that a healthy plant-based diet was associated with significantly slower rates of decline in global cognition (p = 0.032), perceptual speed (p = 0.04), and episodic memory (p = 0.04), specifically in African American participants. A large study conducted in Taiwan concluded that vegetarians had a reduced risk of developing dementia compared to non-vegetarians [144]. Despite the limited number of studies on vegetarian diets, existing evidence suggests that such diets may have a beneficial impact on slowing the progression of cognitive decline. The vegetarian diet is rich in nutrients known for their anti-inflammatory and antioxidant activities. However, it is important to note that patients with cognitive impairment and ADRD may still require a certain intake of animal-derived products, especially meat [145,146]. Indeed, older adults have high protein needs, which will present a challenge when restricting animal product consumption to adhere to a vegetarian diet. These products ensure an important supply of B vitamins that are highly and strictly related to AD development and progression [146].

Table 5

A summary of clinical studies examining vegetarian diet impact on ADRD.

Study Design	Country	Population	Follow-Up	Exposure	Outcome	Results	Covariates	Reference
NS	US and Canada	Vegetarian, n= 72 (32 M 40 F) (62 white, 10 non-white) Age: 76.6 ± 8.3 years Non-vegetarian, n = 60 (24 M 36 F) (44 white, 16 non-white) Age: 73.5 ± 7.7 years	10 years	FFQ, historic dietary habits survey instrument	Verbal learning, memory, attention, processing speed, executive function, visuospatial abilities, language, global cognitive functioning, MMSE, AMNART, and GDS	Vegetarian diet not associated with lower mild memory impairment likelihood. More stable diet associated with better memory/language.	Age, education	[143]
Prospective cohort study	Taiwan	Buddhist Tzu Chi Foundation volunteers Non-vegetarian, n = 3154 (1345 M 1809 F) Age: 57.8 ± 6.3 years Vegetarian, n = 1737 (461 M 1276 F) Age: 58.1 ± 6.5 years	Average 9.2 years	Baseline questionnaires to assess dietary pattern, overall plant-based diet index	MCI and dementia diagnosis	Vegetarians associated with less risk of dementia compared with non-vegetarians after adjusting for covariates.	Gender, age, smoking, drinking, education level, marital status, regular exercise, comorbidities	[144]
Longitudinal	US	n = 3337 (1200 M 2137 F) Age: 73.7 ± 5.72 years African American (AA), n = 2012; white, n = 1325	NS	FFQ	Episodic memory, perceptual speed, and MMSE	plant-based diet associated with slower in GC, PS, and EM in AA but not in white participants. AA in the highest quintile of high plant-based diet had significantly slower rates of GC, PS, and EM than individuals in the lowest quintile.	Age, gender, presence of apolipoprotein E4 (APOE ε4) allele, lifestyle factors (education, cognitive activities, smoking, calorie intake, risk factors for cardiovascular disease, time and interaction time × each covariate)	[141]

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AMNART: American National Adult Reading Test; APOE: apolipoprotein E; EM: episodic memory; FFQ: Food Frequency Questionnaire; GC: global cognition; GDS: Geriatric Depression Scale; MCI: mild cognitive impairment; MMSE: Mini-Mental State Examination; NS: not specified; PS: perceptual speed; VIQ: estimated verbal intelligence; : decline; : increase.

5.1. Impact of Mediterranean Diet on ADRD Prevention

Given the extensive research on the MedD in the management of ADRD, it is reasonable to explore whether it has the potential to prevent the onset of this disease as well. In a study conducted by Hoscheidt et al. [153], normal cognitive participants who adhered to the MedD showed a decrease in Aβ₄₀ levels and a shift in the Aβ_42/40 ratio, indicating a decreased risk of AD development. The results of an epidemiological study conducted by Andreu-Reinon et al. [87] suggest that over a 20-year follow-up period, participants with high adherence to the MedD had a 20% lower risk of dementia compared to those with low adherence. In fact, every 2-point increase in MedD adherence provided an 8% lower risk of developing AD. However, when examining the linear or non-linear trends between adherence to MedD and AD, no statistically significant associations were reported (p = 0.196, p = 0.353). Similarly, the studies conducted by Féart et al. [154] and Hu et al. [155] found no statistically significant association between adherence to the MedD and the incidence of ADRD (p = 0.72). High adherence to the MedD was not associated with a decreased risk of ADRD after 4.1 years of follow-up in an older French population [154] or after 12 years of follow-up in an older Swedish population [72]. On the other hand, the results of the Washington Heights-Inwood Columbia Aging Project conducted by Scarmeas et al. [50] concluded that a one-point increase in the MedD scale decreased the risk of ADRD by 9%. The latest meta-analysis performed by Solch et al. [9] demonstrated a 32% decreased risk of developing ADRD when adhering to the MedD compared to low adherence, with low heterogeneity between studies. The observed beneficial effects of the MedD are attributed to its anti-inflammatory and antioxidant capacities, as well as its high fiber and polyphenol contents, which impact the gut microbiota (Figure 2) [156,157]. The reported discrepancies may be attributed to variations in scoring systems used to define diet adherence, differences in the selected populations’ age, and differences in risk factors for developing AD, as well as the duration of the follow-up and the lack of an AD diagnosis at the beginning of the study period. Despite the reported non-significant effects on ADRD prevention, it is still plausible that some protection is provided through the various mechanisms mentioned earlier. To arrive at evidence-based conclusions, it is imperative to conduct numerous clinical trials, particularly randomized controlled trials, that examine the impact of adherence to the MedD on various AD biomarkers and imaging. Additionally, long-term observational studies starting with a middle-aged population and following them for 12–15+ years are necessary.

5.2. Impact of DASH Diet on ADRD Prevention

There is only one longitudinal study focusing on adherence to the DASH diet and its implication in the development of ADRD in U.S. participants [100]. The study concluded that high adherence to the DASH diet decreases the risk of developing AD by 39%. The observed positive impacts are expected to be the result of long-time use, particularly before the first symptoms appear [158]. To reach a unanimous conclusion about the prevention of ADRD development through the DASH diet, several studies are required, with a special focus on early adherence (in the middle-aged population) and long-term follow-ups (12–15+ years).

The authors would like to thank Florida State University for providing the resources needed to carry out the review work.