Relationships of Dietary Patterns,Foods,and Micro- and Macronutrients with Alzheimer’s Disease and Late-Life Cognitive Disorders: A Systematic Review

Fish and seafood

Table 2 shows selected observational studies published in the last three years and evaluating the relationship among foods, food-groups, and late-life cognitive disorders [42–54]. In particular, the emerging data from the last studies on the correlation between fish and seafood consumption and cognitive decline are conflicting. Significant correlations were found in some particular population subgroups [≥65 years and apolipoprotein E (APOE) ɛ4 carriers]. Age significantly modified the association between fish consumption and cognitive change [42] (Table 2). In fact, no association was observed among adults aged 55–64 years. Conversely, adults aged≥65 years, that consuming≥1 servings/week fish (i.e., 100 g) had a reduction of cognitive decline rate [42]. Compared with individuals who consumed <1 serving/week fish, the mean annual rate of global cognitive decline was reduced by 0.35-point equivalent to the disparity associated with 1.6 years of age. Removing shellfish and/or preserved fish from the total fish did not appreciably alter the results [42].

Interestingly, Morris and colleagues showed that, in APOE ɛ4 carriers, seafood consumption≥β1 meals/week was correlated with lesser burden of brain AD neuropathology, including lower density of neuritic plaques, less severe and widespread neurofibrillary tangles, and lower neuropathologically defined AD [43] (Table 2). Furthermore, some studies demonstrated an association between fish consumption and MRI biomarkers [34, 35] (Table 1). In the Mayo Clinic Study of Aging, higher fish intake was associated with larger cortical thickness summary measures for parietal and average lobar cortical thickness and marginally associated with AD signature cortical thickness, temporal and frontal cortical thickness, and also associated with several individual cortical thickness measures: precuneus, superior parietal, posterior cingulate, supramarginal, middle temporal, and inferior parietal, and marginally associated with fusiform CT [34]. Higher fish consumption was also related with larger total gray matter volume [35]. Fish consumption was also associated with a slower decline in composite and verbal memory scores [42] (Table 2). Of note, Danthiir and colleagues demonstrated that more frequent consumption of total fish (oily and white) was associated with slower cognitive speed for the constructs of inhibition, simple/choice reaction time, reasoning speed, and memory scanning [44] (Table 2). More frequent consumption of oily fish was significantly associated with worse inhibitory processes; similarly, consumption of white fish significantly and negatively predicted simple/choice reaction time [44]. Danthiir and colleagues hypothesized that the negative trends observed between cognitive performance and fish consumption were due to neurotoxic contaminants in fish, such as methylmercury [44]. However, as seen above, Morris and colleagues found that higher brain levels of mercury were not correlated with brain neuropathology [43] (Table 2). Other studies did not suggest evidence that higher fish intake may impact positively cognitive performance in older adults with cognitive impairment [45, 46] or in those cognitively normal [46, 47] (Table 2). However, Dong and colleagues found that cognitively normal Chinese older subjects consumed more fish than MCI subjects [45], and Zhao and colleagues suggested that higher consumption of marine product was associated with a significantly decreased odd of suffering from MCI [47], although in these two Chinese studies, MCI was diagnosed only on the basis of a screening cognitive test (the Montreal Cognitive Assessment - MoCA) and not with clinical criteria (Table 2).

Fruits and vegetables

In Greece, in the EPIC study, among the components of MeDi, only vegetable consumption exhibited a significant inverse association with cognitive decline [27] (Table 1). The diet low in fruit and vegetable might increase the risk of cognitive function decline in older adults [45] (Table 2). In fact, adherence to WHO recommendations for daily intakes of fruit and vegetable, that are eating 5 or more portions of fruit and/or vegetables a day (≥400 g/day), were significantly associated with a 47% decreased prevalence of cognitive impairment [45]. In contrast to these findings, Xu and colleagues found that among older adults (≥68 y) being vegetarian (not eating meat), the risk for cognitive impairment increased almost 4-fold [48] (Table 2). Imaging data in older cohort showed that higher intake of total vegetables was associated with larger dorsolateral prefrontal and superior parietal cortical thickness, while vegetables without legumes were associated with larger middle temporal, superior parietal, and dorsolateral prefrontal cortical thickness [35] (Table 1). In contrast, fruit consumption was negatively associated with inferior parietal, supramarginal, superior parietal, parietal, and precuneus cortical thickness [35]. These findings are in keeping with result of another study in which higher fruit intake was associated with lower temporal and hippocampal volumes [36] (Table 1). This is probably due to high content of simple sugars and a high glycemic index of several fruits and so the effects of carbohydrate component on increased risk of MCI [73]. In older adults, fruit intake would benefit name ability and attention level, while vegetables intake would benefit orientation ability [45] (Table 2). Finally, consumption of green vegetables was independently associated with better memory function and among older elderly (≥68 y) it reduced the risk for cognitive impairment by almost 20% [48] (Table 2).

Nuts

Nuts are rich in PUFA (n-3 and n-6) and MUFA, and also contain a significant amount of minerals, such as phosphorus, potassium, magnesium, calcium, iron, and sulfur, and vitamins, such as B1, B2, B6, and E. It was found the nut intake of MCI patients was less than that of cognitively normal subjects [45] (Table 2). In fact, a study performed on older women found that higher total nut intake (i.e.,≥5/week) over the long term was associated with modestly better cognitive performance [49] (Table 2). Increasingly higher total nut intake was related to increasingly better overall cognition at older age. Considering that one year of age was associated with a mean decline of 0.04 standard units on both the global and verbal composite scores, the mean differences comparing the highest to lowest categories of nut intake were equivalent to approximately two years of cognitive aging [49]. In the same study, it was found a suggestion that those who consumed walnuts 1 to 3 times per month had better cognition than those who consumed walnuts less than once per month, but there was no overall trend of increasingly better cognitive performance with increasing walnut intake [49]. Dong and colleagues also showed that nut intake benefited delayed memory [45] (Table 2).

Coffee and caffeine intake

A recent systematic review suggested that several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men [74]. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident MCI and its progression to dementia were too limited to draw any conclusion [74]. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favorable effects of coffee, tea, and caffeine consumption against AD [74]. Recent findings from the Italian Longitudinal Study on Aging (ILSA) suggested that cognitively normal older individuals who increased their coffee consumption had a higher rate of developing MCI, while a constant in time moderate coffee consumption was associated to a reduced rate of the incidence of MCI [50] (Table 2). Among older adults in Brazil, coffee consumption was associated with better cognitive performance on memory and efficiency of searching in long-term memory (drinking 2–3 cups of coffee per day was associated with about a 3% increase in the mean number of words remembered on the learning, recall, and word recognition tests) [51] (Table 2). Also, drinking≥3 cups/day of coffee was associated with an increase of about 1.23 words in the mean number of words pronounced in the semantic verbal fluency test [51]. However, in this Brazilian study, Araujio and colleagues did not find indication of a dose response relationship in these associations [51]. In the Chinese study on cognitively normal and MCI adults of Dong and colleagues, no significant association was detected between drinking of coffee and cognitive function [45] (Table 2). Another aspect of coffee assumption is the role of its component such as the caffeine. Coffee is a rich source of caffeine, which acts as a psychoactive stimulant. In a cross sectional analysis, Beydoun and colleagues found that caffeine intake was associated with better global cognitive function (MMSE) at baseline for patients≥70 years [52] (Table 2). However, in a study that evaluated the association of caffeine consumption with the cerebrospinal fluid (CSF) biomarkers, particularly Aβ, in AD and MCI patients, no significant difference was found in daily consumption of caffeine between MCI and AD patients, with no correlation between caffeine consumption and Aβ_1-42 in the CSF [53] (Table 2). In the same study, theobromine, xanthine formed upon caffeine metabolism and also directly ingested from chocolate products, was associated with a favorable Aβ profile in the CSF [53]. Interestingly, theobromine in the CSF did not correlate with caffeine consumption, theobromine consumption, or the levels of caffeine and other xanthines in the plasma, but instead it correlated with levels of caffeine, theophylline, and paraxanthine in the CSF, suggesting that it may be formed by central metabolic pathways [53].

Eggs

Eggs have a high content of proteins and lipids, in particular cholesterol. For this reason, they are traditionally considered an unhealthy food. However, eggs have also a significant amount of vitamins A, B6, B12, riboflavin, folic acid, choline, iron, calcium, phosphorus and potassium. In a recent study, higher daily intake of eggs reduced of about 3% the odds of suffering from MCI [47] (Table 2). Instead, in the Chinese study of Dong and colleagues, no significant association was detected between intake of eggs with cognitive function in normal and MCI adults [45] (Table 2).

Tofu

Tofu is a common food in most of the Far East. It is obtained from curdling of the juice extracted from soybeans. It has a high protein and PUFA content. Higher weekly intake of tofu was associated with worse memory performance, furthermore among older elderly (≥68 y), high tofu intake increases the risk (of almost 30%) of cognitive impairment indicative of dementia [48] (Table 2).

Meat

Red meat is a classical element of Western diet that, as mentioned previously, was associated with worse cognitive performance in several imaging studies [37, 41] (Table 1). Consistent with these findings, a negative association of red meat with inferior and superior parietal cortical thickness was found [35] (Table 1). However, this concept should be partially reviewed. In fact, in the last years, eating meat (not being vegetarian) was independently associated with better memory function and in older age (≥68 y) with a four-fold decrease in risk of possible dementia [48] (Table 2). Furthermore, Staubo and colleagues also observed that higher red meat intake was associated with larger entorhinal cortical thickness [35] (Table 1). This effect could also be related to some beneficial components of lean red meat (iron, protein, MUFA, PUFA, cobalamine) and beneficial effects in increasing satiety and reducing weight gain. In the Chinese study of Dong and colleagues, no significant association was detected between intake of light or red meat with cognitive function in normal and MCI adults [45] (Table 2).

Oil

Dong and colleagues, in their Chinese cohort, found that oil intake of MCI patients was less than the normal subjects (29.76 versus 35.20 mL cooking oil per day), and, in particular, would have a positive impact on visual-spatial ability [45] (Table 2). Vegetable oils are rich in carotenoids, and in the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) study carotenoids were associated with higher cognitive performance [54] (Table 2). Extra-virgin olive oil (EVOO) is one of the main elements of MeDi, and clinical trials and population studies indicated that this dietary pattern and its main lipid component EVOO could have a protective role against AD [75].

Legumes

Dong and colleagues, in their Chinese cohort, showed that normal subjects consumed more legumes and legume products than MCI subjects, demonstrating that intake of legumes and legume products would benefit overall cognition level [45] (Table 2). These data were confirmed by imaging biomarkers; in fact, Staubo and colleagues also found that higher intake of legumes was associated with larger parietal and occipital cortical thickness, and with larger thickness in ROIs for superior parietal, inferior parietal, precuneus, and lingual cortical thickness [35] (Table 1).

In their imaging biomarker study, Staubo and colleagues also showed that intake of whole grains or cereals was associated with larger temporal pole and superior temporal cortical thickness [35] (Table 1). Conversely, lower intake of whole grains was associated with higher inflammatory markers (IL-6) and accelerated cognitive decline at older age in the Whitehall II prospective cohort study [41] (Table 1). However, in the Chinese cohort of Dong and colleagues, no significant association was detected between intake of whole grains and cognitive function in normal and MCI adults [45] (Table 2).

3.2.11 Alcohol

Recent findings from the Baltimore Longitudinal Study of Aging suggested that alcohol intake was associated with slower improvement on letter fluency and global cognition among those aged <70 years at baseline [52] (Table 2). Conversely, alcohol intake was associated with better attention and working memory performance, particularly among men and individuals≥70 years at baseline [52]. Compared with moderate consumption (14 to 28 g/d), individuals with higher alcohol intake (>28 g/d) had faster decline or slower improvement on the MMSE, particularly among women and in the older group. Overall, among men, and for those aged≥70 years, lower alcohol intake (<14 g/d) compared with moderate consumption (14 to 28 g/d) was associated with poorer performance in working memory [52]. In the younger group, consuming <14 g/day was associated with slower decline or faster improvement in the letter fluency compared with a moderate intake of 14 to 28 g/day. Similar pattern was showed also for attention and executive functioning [52].

Vitamin E

Table 3 shows selected observational studies published in the last three years and evaluating the association of micro- and macronutrients with late-life cognitive disorders [55–71]. Vitamin E is a potent antioxidant and seems to slow the effects of aging. It is found mainly in nuts, seeds, and oils. Vitamin E is composed by four tocopherols (α-, γ, δ, and β-tocopherols) and four corresponding tocotrienols, and it is known that α- and γ-tocopherols found in foods were linked to slower rate of cognitive decline over a 6-year period [76]. More recently, in the HANDLS study, Beydoun and colleagues investigated the effects on cognitive domains of only one of its isoform, α-tocopherol, showing that vitamin E was positively associated with performance in verbal memory and fluency in the total population, particularly among the younger age group (<48 y) and psychomotor speed among women [55] (Table 3).

Vitamin D

Vitamin D deficiency is a common condition in older adults. Furthermore, the detection of hydroxylases for vitamin D activation and vitamin D receptors in neurons and glia suggested that vitamin D might have a role in cognition. In fact, serum 25-hydroxyvitamin D [25(OH)D] was cross-sectionally associated with reduced Aβ_1-42 concentrations in CSF [56] (Table 3). These findings were on the same line of Mosconi and colleagues showing an association of higher intake of vitamin D with lower Aβ load in AD regions on PET with ¹¹C-Pittsburgh Compound-B (PiB) [57] (Table 3). Vitamin D deficiency was also associated with greater decline in global cognitive function over 4 years of follow-up [58] (Table 3) and with a substantially increased risk of all-cause dementia and AD over a mean follow-up of 5.6 years [59] (Table 3). In particular, vitamin D deficiency was related with significantly faster declines in both episodic memory and executive function performance, the two cognitive domains strongly associated with AD dementia [60] (Table 3). However, Granic and colleagues found a U-shaped relationship between 25(OH)D and global cognitive function and attention in the very old [61] (Table 3). In fact, both low and high season-specific quartiles of 25(OH)D were associated with higher odds of prevalent cognitive impairment, poorer attention reaction times/processing speed and focused attention/concentration, and greater attention fluctuation [61]. Therefore, it could be hypothesized that the neuroprotective effects of vitamin D may be attained only at moderate but not at low or high 25(OH)D concentrations. On the other hand, very old subjects taking vitamin D supplements could be probably only recently advised by their physician to take vitamin D, perhaps due to an underlying vitamin D deficiency condition [77]. Finally, findings from the SU.VI.MAX study suggested a positive association between higher 25(OH)D concentrations and better short-term and working memory only among individuals with low education [62] (Table 3).

Vitamins B and folate

Vitamin B12 deficiency has been associated with neurological and psychiatric symptoms including cognitive impairment [78]. Additionally, vitamin B12, along with folate and vitamin B6, are key actors in the homocysteine cycle, and the disruption of this cycle can lead to elevated homocysteine, which has been found among individuals with dementia [79] and has been shown to predict dementia prospectively [80]. Despite potential biological mechanisms through which B vitamins could play a role in the onset of dementia, results from observational and intervention studies have been inconsistent. In the last three years, in imaging studies, higher intake of folate was associated with higher glucose metabolism on (18)F-fludeoxyglucose (FDG)-PET [57] (Table 3) and greater superior temporal cortical thickness [35] (Table 1). Positive associations were also found between vitamins B1 and B2 and superior temporal and temporal pole cortical thickness, and vitamin B6 and superior temporal and middle temporal cortical thickness [35]. Higher intake of vitamin B12 was also associated with lower Aβ load in AD regions on PiB-PET. The association of vitamin B12 with PiB retention was independent of gender, APOE, and family history [57].

Data collected on 1,354 subjects from three Australian cohorts suggested that participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance when compared to participants with biochemical measurements that were within the normal ranges [63] (Table 3). In the same cohorts, participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance [63]. Furthermore, in the Hordaland Health Study, plasma vitamin B12 concentrations in the lowest quartile (<274 pmol/l) combined with plasma folate concentrations in the highest quartile (>18·5 nmol/l) were associated with a reduced risk of cognitive impairment compared with plasma concentrations in the middle quartiles of both vitamins [64] (Table 3).

In a cross-sectional study on older Koreans, in the AD group, positive associations were observed between vitamin B2 intake and global cognitive status, language, verbal fluency, and verbal and praxis memory; between vitamin B6 intake and global cognitive status, language, verbal fluency, verbal and praxis memory, and constructional praxis; between vitamin B12 intake and global cognitive status, language, praxis memory, and constructional praxis; and between folate intake and praxis memory [65] (Table 3). In the MCI group, vitamin B2 intake was positively associated with global cognitive status and language, vitamin B6 intake was positively associated with language, and folate intake was positively associated with global cognitive status and verbal memory. No associations were observed in the normal group [65]. Finally, in the Women’s Health Initiative Memory Study, folate intake below the recommended daily allowance at study baseline was associated with increased risk of incident MCI/probable dementia, after controlling for multiple confounders [66] (Table 3). There were no significant associations between vitamins B6 or B12 and MCI/probable dementia, nor any evidence of an interaction between these vitamins and folate intake [66].

Polyphenols

Polyphenols are natural bioactive compounds that have been identified in foods and beverages. They are associated with neuroprotective activity probably due to their antioxidant and anti-inflammatory properties. In the inCHIANTI study, in older adults without dementia, high concentrations of total urinary polyphenols were associated with an approximately 47% lower risk of substantial cognitive decline in global cognitive function and an approximately 48% lower risk of substantial cognitive decline in attention over a 3-year period, but not with executive function. No significant association was found between total dietary polyphenols and any cognitive test [67] (Table 3).

Carotenoids

Carotenoids are ubiquitous colored pigments, found mainly in fruits and vegetables such as kiwi, carrots, and tomatoes or in green leafy vegetables. Among carotenoids, positive association was found between higher intake of β-carotene and dorsolateral prefrontal and temporal pole cortical thickness [35] (Table 1) and with higher glucose metabolism on FDG-PET [57] (Table 3). However, the β-carotene levels were related with reduced glucose metabolism for women, APOE ɛ4-carriers, and participants with positive AD family history [57].

Among carotenoids, findings from the Three-City-Bordeaux cohort suggested that higher lutein concentration, considered as a function of plasma lipids, was consistently significantly associated with a decreased risk of all-cause dementia and AD [68] (Table 3). Moreover, in the SU.VI.MAX study, a carotenoid-rich dietary pattern (CDP) strongly correlated with the plasma status of β-carotene, α-carotene, β-cryptoxanthin, and lutein, was positively correlated with the consumption of green-colored fruits and vegetables, vegetable oils, orange-colored fruits and vegetables and soup, and was negatively correlated with that of beer-cider and wine. CDP score was negatively associated with alcohol and protein intake and positively associated with carbohydrate intake [54] (Table 2). Furthermore, CDP score was positively associated with the composite cognitive performance score assessed 13 years later. More specifically, higher CDP scores were related to better episodic memory, semantic fluency, working memory, and executive functioning [54].

Capsaicin

Capsaicin is a micronutrient acting as an active component of chili peppers. In recent studies, it has been shown to have favorable effects on various diseases including atherosclerosis, CVD, cancer, obesity, gastrointestinal diseases, hypertension, and stroke, and also reducing total and cause-specific mortality [81, 82]. Liu and colleagues, in a cross-sectional study collecting the dietary habits of participants in 12 months, found that capsaicin-rich diet was associated with MMSE and serum Aβ₄₀ levels, but not with serum Aβ₄₂ levels [69] (Table 3). A possible explanation may be that neurons produce more Aβ₄₀ than Aβ₄₂ and serum Aβ₄₂ levels have higher cerebral tropism with increased capacity of aggregation in the brain, so it is less prone to efflux from the brain to blood.

Macronutrients: Fatty acids

Many epidemiological studies have demonstrated that dietary fatty acids may play a key role in several pathological conditions. In particular, an increasing body of epidemiological evidence suggested that elevated SFA could have negative effects on MCI [11], while a clear reduction of risk for cognitive decline has been found in population samples with elevated fish consumption, high intake of MUFA and PUFA, particularly n-3 PUFA [11]. In fact, it is of extreme nutritional importance the intake of essential fatty acids from both the n-3 and n-6 series of PUFA. In the n-3 series, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are considered the most important. In particular, DHA might affect the neuronal survival. In agreement with this hypothesis, Baierle and colleagues showed that cognitive function was positively associated with DHA, nervonic acid (MUFA), and total n-3 PUFA, while was inversely related to myristic acid (SFA), palmitic acid (SFA), palmitoleic acid (MUFA), the n-6 PUFA/n-3 PUFA ratio, and homocysteine levels [70] (Table 3). In this study, elevated levels of homocysteine were also inversely associated with total n-3 PUFA which may lead to vascular disease and, thus, may be involved in the risk of cognitive decline and other brain dysfunctions. Therefore, balanced intake of both n-3 and n-6 fatty acids may be essential for health by avoiding a harmful permanent proinflammatory state. These data are supported also by recent imaging studies. In fact, positive associations (higher intake with larger cortical thickness) were observed for n-3 PUFA and linolenic acid (n-3 PUFA) with superior temporal cortical thickness and for linoleic acid (n-6 PUFA) with superior temporal, precuneus, middle temporal, and parietal cortical thickness [35] (Table 1). Furthermore, in postmenopausal women study, n-3 index [red blood cell (RBC) EPA+ DHA levels] was directly associated with the total brain and hippocampal volumes. In particular, a 2 standard deviation (SD) (3.2% absolute) higher n-3 index was associated with a 0.48% (4.2 cm³) larger total brain volume measured 8 years later [71] (Table 3). A marginally significant association between a 1-SD increase in DHA with total and normal brain volume has also been found, instead no association was found for EPA [71]. Furthermore, Pottala and colleagues showed that higher levels of RBC EPA+ DHA were associated with 50 mm³ larger hippocampal volumes [71]. Furthermore, higher intake of n-3 PUFA was associated with lower Aβ load in AD regions on PiB-PET, independently of gender, APOE, and family history [57] (Table 3). On the contrary, in another study, in normal older adults, higher proportions of long-chain n-3 PUFA did not give benefits on cognitive performances [44] (Table 2). Higher concentrations of EPA were associated with poorer perceptual and reasoning speed in females, but not in males, before controlling for current fish intake [44]. Therefore, it is plausible that a physiologically different effect of long-chain n-3 PUFA in relation to gender may lead to differential associations with cognition [44].

Dietary patterns and late-life cognitive disorders: Possible mechanism models

We need to pursue studies which will improve the knowledge of the biochemical mechanisms underlying the pathophysiological processes and, in a public health perspective, will examine dietary patterns. These mechanisms could be searched at the different levels of investigation of dietary factors linked to late-life cognitive disorders used in the present review article (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients). Consumption of the western diet contributes to the development of chronic conditions, such as atherosclerosis, diabetes, obesity, hypertension, and hyperlipidemia, which in turn results in metabolic, inflammatory, and microvascular changes that induce injury to the white matter of the brain [83, 84]. Subsequently, white matter disease promotes the development and progression of cognitive decline and dementia [85].

There is converging evidence that composite dietary patterns, such as the MeDi, are related to lower risk for CVD, dyslipidemia, hypertension and coronary artery disease, several forms of cancer, cognitive decline, and overall mortality [86, 87]. Several mechanisms have been proposed underlying the suggested protective role of the MeDi against age-related changes in cognitive function, predementia syndromes and dementia: vascular variables and non-vascular biological mechanisms such as metabolic, oxidative, and inflammatory processes [88]. Therefore, MeDi may act on cognition through cerebrovascular mechanisms. Alternatively, AD almost certainly has its pathological origins in midlife, and it is possible that components of the MeDi could affect the metabolism of Aβ or tau protein [89]. Moreover, the model of “gene environment interaction” may be also considered, in light of the recently proposed Latent Early Life Associated Regulation model, in which environmental agents, such as heavy metals and toxins, and dietary factors, could perturb gene regulation in a long-term fashion, beginning at early developmental stages, but these perturbations do not have pathological results until significantly later in life [90].

The DASH is a diet that has been shown by randomized clinical trials in the US to protect against many cardiovascular risk factors of dementia [91]. Some of the protective effects of DASH included lower blood pressure [92] and blood low-density lipoprotein (LDL) cholesterol levels [93], weight reduction [94], reduced oxidative stress and inflammation [95], improved insulin sensitivity and reduced incidence of diabetes mellitus [96]. DASH diet and the MeDi have many similar components, such as emphasis on natural plant-based foods and limited consumption of red meat, but there are differences. The MeDi is a cultural diet that uniquely emphasizes daily intake of olive oil (MUFA), fish, and potatoes, and moderate wine consumption, whereas DASH uniquely emphasizes dairy consumption and restricted intake of sodium, commercial sweets, and saturated fat.

The MIND diet is a refinement of the extensively studied cardiovascular diets, the MeDi and DASH diets, with modifications based on existing studies relevant to nutrition and associated with dementia prevention. MIND diet is not specific to the underlying AD pathology, but perhaps better overall functioning and protection of the brain. A number of prospective cohort studies found that higher consumption of vegetables was associated with slower cognitive decline with the strongest relations observed for green leafy vegetables [12]. Green leafy vegetables of MIND diet are sources of folate, vitamin E, carotenoids, and flavonoids, micronutrients that have been related to lower risk of dementia and cognitive decline [31, 32].

Foods, food groups, and late-life cognitive disorders: Possible mechanism models

Fish consumption has been associated with lower risk of AD because it could have a preventive effect against dementia through its anti-thrombotic and anti-inflammatory properties in addition to its specific effect on neural functions, an effect thought to be mediated through altering gene expression [97]. Furthermore, the favorable effects of fish oil on cerebrovascular function are known, in particular for the impact of DHA on endothelial nitric oxide synthase (eNOS) expression and a lower risk for ischemic stroke [98]. It was hypothesized that some negative epidemiological findings observed for the impact of fish consumption on cognitive performance may be due to neurotoxic contaminants in fish, such as methylmercury [44]. However, as seen in one of the reviewed studies, higher brain levels of mercury were not correlated with brain neuropathology [43]. Diet may affect trace metal concentrations in the brain of subjects with normal cognition [99] or AD [100–102], and transition metals, though crucial to many biochemical neuronal processes, were abnormally aggregated and distributed in AD [103, 104]. Dyshomeostasis in aluminum, silicon, lead, mercury, zinc, iron, and copper have been reported in AD brains, where the abnormal accumulation and distribution of the latter three may elicit oxidative stress and macromolecular damage, impeding cellular function [104–107]. However, considering recent advances in neurobiology of metals, the complex correlation between biometal metabolism, genetics, and the environmental and the pathophysiology of many neurodegenerative diseases [106, 107] warrants further investigation.

In recent years, numerous preclinical studies involving fruits, nuts, and vegetables have identified potential beneficial effects to brain health and cognition resulting from their nutrient and non-nutrient phytochemical content. These phytochemicals have the ability to alter cellular function by modulating transcription factors and altering the expression of genes, cellular metabolism, and cellular signaling [108]. In vitro and in vivo studies have firmly established the mechanistic effects of these phytochemicals on cognitive function, with many studies demonstrating their ability to counter oxidative stress [109], inflammation [110], as well as promote neuronal signaling and regulate transcription [111]. In the past five years, there has been an increasing interest in the role that gut microbiota may play in the modulation of the bidirectional signaling underlying the gut–brain axis [112, 113]. In particular, in an Irish study, there was an association between indicators of general health, including frailty and MMSE, and microbiota composition only in long-stay subjects [114]. It has been also suggested that diet and specific nutrients can affect the composition of the gut microbiota [115] that might influence the production or aggregation of Aβ protein in AD pathogenesis [116]. Bacteria populating the microbiome have been shown to produce amyloids, lipopolysaccharides, and other immunogenic compounds [117, 118] that might contribute to the regulation of signaling pathways implicated in neuroinflammation, brain Aβ deposition, and AD pathogenesis [116]. Plant-derived nutrients and phytocompounds, by ameliorating gut inflammation and dysbiosis, might stimulate a positive modulation of the gut–brain axis, reduce neuroinflammation, and retard or regress cognitive impairments associated with AD [119]. Additionally, high intake of plant foods and specific plant-derived compounds have been shown to reduce Aβ aggregation and, for this reason, are currently considered suitable for the prevention of AD, as showed in some selected studies of the present systematic review [34, 57].

Caffeine, as an antioxidant substance, was revealed to reduce oxidative stress [120] and also to protect against the disruptions of the blood-brain barrier [121]. Most of the biological effects of caffeine, including those on the brain and the central nervous system, are mediated through antagonism of the adenosine receptors, specifically the A1 and A2A receptors [122]. Other complementary mechanisms of caffeine action that could contribute to its cognitive benefits in AD mice are the ability of caffeine to decrease hippocampal levels of pro-inflammatory cytokines [e.g., tumor necrosis factor-α, interleukin (IL)-12(p70), and interferon-γ) [123], caffeine’s beneficial effects on signal transduction factors is involved in neuronal plasticity and survival [124], and the ability of caffeine to enhance brain mitochondrial function [125].

Micronutrients, macronutrients, and late-life cognitive disorders: Possible mechanism models

Optimal micronutrient status would moderate the deterioration in brain integrity. Autophagy is probably a crucial and a major process in the preservation of brain integrity. Micronutrients (vitamins, trace-elements, and also antioxidants) most likely affect brain integrity by normalizing efficient autophagy [126]. Multiple lines of evidence indicate that oxidative stress not only strongly participates in an early stage of AD prior to cytopathology, but it plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promote the development of AD. Exogenous anti-oxidants (such as vitamin E and C, carotenoids, flavonoids) decrease free radical mediated damage caused by toxic chain reactions in neuronal cells and reduce the toxicity of Aβ in in vitro studies of brains of patients with AD [127].

There is a vast literature demonstrating neuroprotection of the brain by vitamin E, rich sources of which are vegetable oils, nuts, and whole grains [128]. In particular, vitamin E might exert a regulatory effect on cell proliferation and a beneficial effect in improving glucose transport and insulin sensitivity [129]. Most of the known actions of flavonoids are related to their antioxidant properties that can include suppression and scavenging of reactive oxygen species, and upregulation of antioxidant defenses, the control of neuronal survival, death, and differentiation, long-term potentiation, and memory as well as the effect on gene expression and interactions with mitochondria [130]. Therefore, flavonoids, lead to increased NO bioavailability in the vasculature of the hippocampus and subsequent angiogenesis and neurogenesis.

It has now been proven that vitamin B6, vitamin B12, and folate deficiency, as co-factors in the methylation of homocysteine, are associated with increased homocysteine concentrations. Supraphysiological concentrations of homocysteine or deficits in folate and vitamin B12 should promote Aβ and tau protein accumulation and neuronal death, and also have a direct effect on cognitive decline. The potential mechanisms whereby homocysteine might mediate cognitive decline and dementia include: neurotoxicity induced by activation of N-methl- D-aspartate receptors, promotion of apoptosis, vascular injury from promotion of atherogenesis making vascular endothelium prothrombotic and proliferation of smooth muscle cells, platelet activation, and increased burden of ischemic strokes and white matter lesions [131].

Epidemiologic investigations have revealed a beneficial role of vitamin D in muscle function, cardiovascular health, diabetes, and cancer prevention. Low levels of serum 25(OH)D are also associated with increased odds of prevalent cognitive dysfunction, AD and all cause dementia in a number of studies. Vitamin D contributes to neuroprotection by modulating the production of nerve growth, neurotrophin, glial cell derived neurotrophic factor, nitric oxide synthase and choline acetyl transferase [132], and neuroprotective mechanisms including vasoprotection and Aβ phagocytosis and clearance [133, 134].

Several mechanisms have been postulated for the possible protective role of n-3 PUFA in dementia [77]. Supplementation with n-3 PUFA may have cognitive benefits based on animal studies showing neuroprotection through anti-oxidant, anti-inflammatory and anti-amyloid effects. DHA, the predominant n-3 PUFA in the brain, is a key component of membrane phospholipids in the brain and adequate n-3 PUFA status, coming from dietary consumption, may help maintain integrity and neuronal function [135]. Secondly, n-3 PUFAs appear to have effects on dopaminergic and serotonergic systems [136]. The oxidative products of PUFA act as key cellular mediators of inflammation, allergy and immunity, oxidative stress, bronchial constriction, vascular response, and thrombosis, and may thereby influence risk especially for vascular dementia. DHA may be directly involved in enhancing neuronal health in the aging brain through a range of potential mechanisms. In particular, it increases cell viability via neuroprotective and antiapoptotic mechanisms, while also promoting dendritic arborization and synaptogenesis [137]. DHA may modify the expression of genes that regulate a variety of biological functions potentially important for cognitive health, including neurogenesis and neuronal function [138]. Long-chain n-3 PUFA have been shown to reduce Aβ formation and oxidative damage [139]. Higher intakes of saturated and trans fat and lower intakes of mono- and polyunsaturated fat can contribute to insulin resistance and an atherogenic lipid profile [140]. Moreover, insulin resistance, high insulin levels, and cholesterol are all implicated in Aβ accumulation in the brain, the pathologic hallmark of AD [141]. In a very recent neuropathological metabolomic-based study, in the brains of patients with varying degrees of AD pathology (healthy brains, brains with AD pathology but without cognitive symptoms, and AD brains), significant differences in the abundance of six unsaturated fatty acids were identified in three brain regions both vulnerable and resistant to classical AD pathology, with gradations in these metabolites being related to both severity of neuropathology at death as well as domain-specific cognitive performance during life [142]. These findings suggested that dysregulation of unsaturated fatty acid metabolism may play a role in driving AD pathology, providing with further evidence for the metabolic basis of AD pathogenesis.