I need to write review research papers.

Review

Nutrition: Review on the Possible Treatment for Alzheimer’s Disease

Benson O.A. Botchway a,b

, Masania K. Moore b , Ishwari C. Iyer

b ,Faith O. Akinleye

b , Marong

Fang a,*

a Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China

b School of Basic Medical Sciences, Zhejiang University, Hangzhou, China

Accepted 17 October 2017

*Correspondence to: Prof. Marong Fang, Institute of Neuroscience, Zhejiang University School

of Medicine,866 Yuhangtang Road, Hangzhou, 310058, China.Tel.: (+86)-571-88208160;Fax.:

(+86)-571-88208094; E-mail: [email protected]

ABSTRACT

Since its discovery some hundred years ago, Alzheimer’s disease (AD), a neurodegenerative

disease and an eminent cause of most dementia, continues to pose problems for affected families

and society, especially in developed countries. With the approved medications by the Food and

Drugs Administration in the United States, effectual treatment of AD apropos to the complete

eradication of the disease continues to be elusive due to complexities relating to the

pathophysiology of the disease. Nutrition has and continues to play a salient role in the survival

of living organisms with no exception for human beings. Herein, we report the connection

between nutrition and AD with particular attention to vitamins, curcumin, and the Mediterranean

diet.

Keywords: Alzheimer’s disease, curcumin, dementia, Mediterranean diet, neurodegenerative,

nutrition, vitamins

INTRODUCTION

Alzheimer’s disease (AD) is one of many neurodegenerative diseases, including Parkinson’s

disease, Huntington’s disease, and normal pressure hydrocephalus [1]. AD continues to pose a

great challenge to the aging community, especially those in developed countries. In our previous

published report, we explicated the history of the disease as well as ongoing developments

regarding treatment methods along with other currently researched therapeutics. The

contemporary authorized medications for AD, rivastigmine (brand name: Exelon, 2000),

galantamine (brand name: Razadyne, 2001), memantine (brand name: Namenda, 2013),

anddonepezil and memantine (brand name: Namzaric, 2014), are not as effectual as expected

owing to the fact that they only slow down the inevitable [1]. A few months back, Solanezumab,

a monoclonal antibody that showed stupendous potentiality as being future therapeutic for mild

AD, failed in its final clinical trial, Expedition 3. Though the drug, to some extent, might have

inhibited soluble amyloid-β (Aβ), the cognitive decline associated with the disease was not

statistically conspicuous when the treatment group was compared to the placebo group [2]. With

that said, the intricacies encompassing the disease makes concocting an effective treatment

laborious.

Humans need adequate nutrition in order to survive since nutrition can aid in the obviation of

maladies. Proteins, carbohydrates, and fats are three of the salient nutrients the human body

needs for survival, with the other nutrients being vitamins and minerals, fiber, and water. All

these nutrients can be derived from disparate food sources and play diverse roles in the human

body. Proteins, derived from food sources such as cereals, beans, meat, fish, eggs, and nuts, have

the capacity to aid in building the body. Carbohydrates have the potentiality of serving as

anticoagulants, antigens, and hormones as well as assisting in blood glucose regulation, ketosis

prevention through disintegration of fatty acids, and provision of energy to body tissues. Some

food sources of carbohydrates include cottage cheese and potatoes. Fats, the other macronutrient

after proteins and carbohydrates, also provide energy to the body along with other several

functions, such as curbing of the body’s homeostasis. The two prominent fats are omega-3fatty

acid (alpha-Linolenic acid) and omega-6 fatty acid (Linoleic acid) [3].

It is worth noting that food nutrients have to be consumed in their right proportions.

Recommended Dietary Allowance (RDA) is generally the amount of quintessential food

nutrients deemed to be apposite to meet the nutritional needs of healthy individuals [4]. The daily

RDA for carbohydrates and proteins in an adult male (aged 19 years and upwards) is 130 grams

and 56 grams, respectively. In non-pregnant adult females, it is 130 grams (for carbohydrates)

and 46 grams (for proteins). Additionally, in pregnant adult females and women in lactation, the

daily suggested carbohydrate quantity is 175 grams and 210 grams respectively with the daily-

recommended protein amount being 71 grams for both groups. Regarding essential fatty acids

(i.e., linoleic and alpha-linolenic fatty acids), RDA for linoleic and alpha-linolenic acids for both

males and females (aged 9 years and upwards), as well as pregnant females and females in

lactation period is in the range of 10–17grams per day and 1.0–1.6 grams per day, respectively

[4]. With the daily-recommended amount of these macronutrients in mind, excess consumption

of carbohydratescould result in increased risk ofdiabetes as evidenced in a recent study [5].

Conditions such as obesity, type 2 diabetes, and hypertension are linked to high intake of fats [6].

The connection between nutrition and AD has been discussed in several published studies. In

some quarters, curcumin, vitamins, and Mediterranean diet have been postulated to possibly have

a preventative role in AD [1, 7–9]. As such, this review report was centered on these three

nutritional components.

VITAMINS

AD has been recognized as the most studied and common cause of dementia. As there is still

no known cure for it and with current drugs providing little to no alleviation for patients,

researches reiteratively indicate that the principal strategy of treating AD might be through

optimal dieting and exercising. The use of vitamin supplementation as an adjuvant intervention

has been examined, some of which have been postulated to be effective [7]. Lopes et al.’s [10]

systematic review suggested that vitamins, among other nutrients, play an extensive role in the

development of AD treatment and management as an examined AD population had significantly

lower plasma levels of folate as well as vitamins B12, C, and E in comparison to a controlled

population. The study also concluded lower levels were indications of patients with AD, possibly

having impaired systemic availability of several nutrients [10].

Antioxidants are molecules that inhibit oxidation of other molecules. They are widely

employed and investigated for preventative benefits to diseases including AD, along with other

neurodegenerative conditions. Antioxidants protect against extracellular and intracellular

reactive oxygen species (ROS) and H2O2-cell-damaging radicals, which are byproducts

generated from normal cell metabolism [11]. Exogenous chain breaking antioxidants vitamin E

(α-tocopherol), vitamin C, and retinoic acid lowers free-radical-mediated damage caused by

toxic chain reactions in neuronal cells, thus aiding in the inhibition of dementia pathogenesis in

mammalian cells [12]. Also, vitamin D exhibits antioxidant properties that abate free-radical-

mediated damage in neuronal cells, thereby assisting in the impediment of dementia and

cognitive impairments [13]. Additionally, nicotinamide, a sirtuin inhibitor and the amide form of

vitamin B3 (niacin), is the precursor for coenzyme β-nicotinamide adenine dinucleotide (NAD + )

and is necessary for cellular function and energy metabolism. Nicotinamide treatment has been

evinced to prevent cognitive deficits while improving short-term spatial memory in an AD

mouse model, thus explicating potentiality as an AD therapy [14].

Vitamin A

Vitamin A, regarded as one of the most multifunctional vitamins, succors in embryonic

growth and development, immune competence, reproduction, conservation and maintenance of

epithelial surfaces as well as proper functioning of adult brain [15]. Low levels of vitamin A are

a risk factor for AD and a major problem in the aging population. A number of genes implicated

in AD are maintained in the immune system by vitamin A [16]. The most useable form of

vitamin A is retinol, which is converted by the body into retinal and retinoic acid (RA). In AD,

there have been observations on the transport of retinoid from the intestine to target tissues,

including the brain, being modified. Though distribution of RA within a mature human central

nervous system is unknown, coupled with the impossibility of sampling live human brains as

well as the rapid degradation of RA in autopsied brains, there is, albeit, indirect evidence

endorsing lowered concentration of retinoic acid in AD brain. On the other hand, the enzymatic

synthesizer of RA, retinaldehyde dehydrogenase (RALDH), has also been found to be elevated

in AD brains, which further warrants the theory of AD patients having lower levels of RA. In

occurrences where neuronal cell lines have been deprived of retinoid, higher levels of RALDH

have been exhibited. However, these high levels would have been normalized by the addition of

retinol through feedback mechanisms in healthy patients [17].

Vitamin B

Vitamin B, a notable contributor to the regulation of healthy levels of the amino acid,

homocysteine (HCy), also plays a synergistic role in the maintenance of cardiovascular and

neural health [18]. In several aspects, information and controlled trial research efforts in this area

has been conclusively limited. Majority of sources explored focused on a small subset of vitamin

B (folate, vitamin B12, and, to a lesser extent, vitamin B6) as they play the most obvious role in

HCy metabolism. Thus, the multifaceted inter-related roles of the other vitamin Bs have been

largely overlooked.

Nicotinamide (vitamin B3) participates in cellular energy metabolism, influences oxidative

stress, and modulates multiple pathways that are tied to cellular survival and death. This resilient

cytoprotectant blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine

exposure and late nuclear degradation during disorders, including immune system dysfunction,

diabetes, and age-related diseases [19]. Studies showed nicotinamide treatment to improve

cognitive performance, along with extenuation of Aβ and hyperphosphorylated tau pathologies in

both the hippocampus and cerebral cortex of AD mice. Preserved mitochondrial integrity,

improved autophagy function, and declined neuronal vulnerability to oxidative stress were also

noted. Vitamin B3 presents extraordinary optimism in the development of dietary AD therapy

and is expected to be further canvassed [20].

Vitamins B6, B9 (folate), and B12 have also been explored as possible therapeutic treatments

for AD. These vitamins are inextricably linked due to their complementary roles in ―folate‖ and

―methionine‖ cycles [21]. It is, nonetheless, important to note that the existence of inadequate

statistical control for dietary cofounders such as antioxidants and other vitamin B’s gives rise to

inconsistent findings. Folate, for example, is correlated with other various preventative factors in

AD therapy, which could possibly account for cofounding partiality. Such dietary cofounders

should be carefully examined in requisite prospective studies so as to limit conflicting results [18,

22-23].

Vitamin C

Vitamin C (ascorbic acid) is a water-soluble antioxidant that prevents lipid peroxidation in

biological systems and acts as a major defense against free radicals in whole blood and plasma.

Like other antioxidant vitamins, plasma levels of vitamin C were found to be significantly

curtailed in patients with AD despite adequate intake of this vitamin in diets. This concurred with

the fact that antioxidant vitamins offer protection against damage instigated by oxidative stress

[24]. The relationship between AD and vitamin C has been investigated in large population

studies and clinical trials. Reports have evidenced neurodegenerative diseases, which exhibit

high oxidative stress, to constantly consume ascorbic acid available in the brain, subsequently

culminating in the oxidation of vitamin C. Additionally, in the presence of high levels of ROS,

vitamin C becomes unavailable to modulate neuronal metabolism. Hence, breakdown of

homeostatic systems for ascorbic acid recycling, oxidative stress, and elevated ROS production

are essential aspects in the progression of neurodegeneration, more specifically AD. It is

important, however, to note that avoiding vitamin C deficiency is likely to be more beneficial in

having a protective function against age-related cognitive decline and AD than taking

supplements in an already healthy diet. This is due to the ability of the transport of ingested

vitamin C from the intestines into blood being limited by saturable sodium-dependent vitamin C

transporter, subsequently resulting in the use of supplements being erroneously thought of

having greater benefit than they really do [25-27].

Vitamin D

Vitamin D, a steroidal hormone, is important for physiological function and protection of the

central nervous system as well as regulation of bone metabolism [28]. Deficiency in vitamin D is

known to decrease bone density coupled with increasing risk of copious common forms of

cancer and cognitive impairment in both young and old adults [29]. The active form of vitamin D,

1, 25 dihydroxy-vitamin D3, upregulates neurotrophin expression and glial-derived neurotrophic

factor, while hypovitaminosis D has been associated with prevalent cognitive impairment and

AD in older people [13].

The connection between vitamin D dearth and AD has been made, where studies have

discovered vitamin D levels to be conspicuously subservient in comparison to normal controls.

What is more, vitamin D depletion has been linked to brain atrophy owing to inflammation of the

different types of vitamin D receptors. A strong relationship between overexpression of either

vitamin D receptors or vitamin D supplementation and the suppression of amyloid-βprotein

precursor (AβPP) has also been noted [13, 24, 28, 29].

One study demonstrated vitamin D3 supplementation improved cognition and memory in

patients with moderate AD receiving memantine, which might be contingent on the synergistic

neuroprotective effect of memantine plus vitamin D. This phenomenon typifies a new multi-

target therapeutic class for AD treatment [30]. Besides, vitamin D affects several mechanisms of

AD pathogenesis including production, clearance, phagocytosis, and enzymatic degradation of

Aβ peptides as well as tau phosphorylation [31]. Supplementation with vitamin D has been

postulated to ameliorate cognitive deficit, more specifically AD. It is expected that detailed

investigation apropos to the link between several gene-environment interactions and their

influence on AD progression along with metabolic and endocrine etiological factors would be

explored [30-32].

Vitamin E

Vitamin E represents antioxidants, with α-tocopherol being the most active form. Vitamin E

has antioxidative potential and protects lipids from peroxidation in membranes. Thus, vitamin E

supplementation has been suggested to be beneficial in AD. On top of that, vitamin E molecules

exert neuroprotective, anti-inflammatory, and hypocholesterolemic properties [33, 34] coupled

with its ability to modulate gene expression by influencing various transcriptional pathways [33].

Again, studies found vitamin E to suppress tau-induced neurotoxicity and provided a palpable

level of neuroprotection against increased oxidative stress induced by Aβ plaques, a known risk

factor for neuronal death and resultant brain injury in AD [35]. Additionally, vitamin E

deficiency can lead to destruction of neurons and has been insinuated in cases of cerebellar

atrophy, with curtailed vitamin E levels being found in the plasma of both AD patients and

individuals with mild cognitive impairment. Inversely, higher plasma concentrations of vitamin

E and improved dietary intake of either vitamin E or α-tocopherol equivalents have been linked

to abridged AD risk [36].

CURCUMIN (TURMERIC)

Turmeric is a culinary spice used in Bangladeshi, Indian, Pakistani, and Iranian cuisines. It is

derived from Curcuma longa, a perineal plant of the ginger family. The rhizomes of these plants

are first boiled for about an hour so as to make them soft. They are then dried under the sun for

10-15 days and subsequently ground into powder [37]. Turmeric has been used extensively in

Hindu traditional medicine, Ayurveda, for many years. The major yellow pigment in turmeric is

what is referred to as curcumin [38].

Regarding the structure (Fig. 3), curcumin is non-steroidal and polyphenolic. In terms of

mercantile, composition of curcumin is postulated to be a potpourri of 77% curcumin, 18%

desmethoxycurcumin, and 5% bisdemethoxycurcumin [39].

Several epidemiological and clinical studies have revealed the baulking features of turmeric

in AD as well as the potentiality of ameliorating AD [8]. Interestingly, the ubiquity of AD among

70-79-year-old people in India is 4.4 times less than that of adults within the same age range in

the United States [40].

Polyphenols

Curcumin are flavonoids that fall under the group of polyphenols. Though this review report

focuses on curcumin, it would be worth noting the varying roles of the different types of

flavonoids. Table 1 accounts for some of the different types of flavonoids along with their

mechanism of action and bioavailability.

Grape-seed polyphenolic extract has been demonstrated to attenuate tau proteins. Tau

proteins, when folded abnormally, leads to formation of paired helical filaments (PHF) and

neurofibrillary tangles. Aggregation of these tangles contributes to AD. PHF enter cells by fluid-

phase endocytosis. PHF in turn induces misfiling of tau protein [41]. Flavonoids have been

evinced to curtail the formation of PHF and neurofibrillary tangles [42]. Also, mutations in

PSEN-1, APP, and PSEN-2 genes result in AD [43]. Studies have shown Capparis spinosa, a

flavonoid-rich plant, to downregulate the expression of APP, PSEN-1, and PSEN-2 [44]. More

so, Vaccinium myrtillus anthocyanoside (VMA), a mixture of 15 different flavonoids, curbs the

formation of Aβ peptide fibrils in vitro [45],as well as subverts oxidative stress[46]. In a study

conducted by Wang et al., the authors evinced improvement in cognitive functions of mice

suffering from AD. In that study,a polyphenolic preparation derived from grape (GP) was

employed. Proanthocyanidin, a component of this polyphenol, has been correlated with cAMP

response element binding protein (CREB) in the hypothalamus. CREB is associated with

learning and memory. In view of this, GP could enhance higher brain functions (cognition) [47].

Again, Aβ results in the activation of caspase 3 and release of cytochrome c. This increases ROS

[48]. Monoflavonoids have shown to decrease Aβ toxicity by repudiating the activation of

caspase-3 and release of cytochrome c. Thus, curtailment of oxidative stress by monoflavonoids

could obviate neuronal death[49].

Action of Aβ plaques

Aβ plaques are neurofibrillary tangles of the Aβ protein found in the brains of patients with

AD. Aβ oligomers are highly precarious. There is the notion that they form ion channels and

increase the influx of calcium ions in the brain [50].There is also the proposition that Aβ

oligomers decrease glucose metabolism in the brain by competing with insulin for binding to

insulin receptors [51]. Both mechanisms result in the apoptosis of brain cells. In view of this, Aβ

protein plays a significant role in AD.

Aβ is formed via the cleavage of AβPP byβ- and γ-secretases. Studies have shown that

curcumin lowers Aβ protein levels by interfering with the maturation of AβPP. Neuronal cells of

mice were employed in probing curcumin’s effect on Aβ levels. The obtained results connoted

that curcumin treatment fomented in the reduction of AβPP endocytotically, along with abating

Aβ levels [52].

Curcumin and vitamin D work hand-in-hand to augment the brain’s immune system, thereby

protecting it against Aβ plaques. While curcumin increases the surface binding of the Aβ plaques

to macrophages, vitamin D stimulates the absorption of Aβ plaques in macrophages. Researchers

have found that curcumin alone cannot work efficiently, as it would break down before serving

its purpose. Thus, a novel synthetic curcumin was introduced to patients with AD. The synthetic

curcumin, developed by the Human BioMolecular Research Institute, manifested better results

owing to the fact that it absorbed more readily [53]. What is more, by virtue of its

hydrophobicity, curcumin could readily cross the blood-brain barrier and exert its effects [54].

Action on glial cells and macrophages

Macrophages are agranulated cells of the immune system (leukocytes) known for their

adroitness in migrating and engulfing pathogens [55]. Glial cells (especially microglia) form the

immune system of the central nervous system (CNS) [56]. Microglia scrutinizes the CNS and

keep check on plaques by activating T-cells of the immune system [57].

Curcumin helps macrophages clear Aβ plaques in the brain of AD patients. The macrophage

of six AD patients and three controls were treated with curcuminoids in vitro. At the start of the

study, the Aβ plaques uptake by the macrophage of AD patients was significantly subservient to

the macrophages of the control group. Following treatment with curcuminoids, the uptake of Aβ

plaques by the macrophages was conspicuously increased in 50% of the patients [58]. Also,

curcumin has been discovered to increase the expression of gene coding for cathelicidin

antimicrobial peptide (CAMP) by three folds. CAMP, due to its antimicrobial properties, battles

against bacteria, viruses, and fungi, thereby playing an important role in inducing the activity of

macrophages in the obliteration of Aβ plaques [59].

Anti-inflammatory effects

Inflammation is defined as the body’s response to irritation or injury, aimed at eliminating

both foreign and endogenously derived contaminating agents. Although no clear consequence of

inflammation in the pathogenesis of AD has been noted, it has, nonetheless, been discovered that

both acute and systemic inflammation morbidly speeds up the progression of AD through the

elevation of TNF–α serum levels, which in turn exacerbates cognitive diminution in AD [60].

Increase in the accumulation of amyloid peptide and activated microglia in the brain causes

chronic inflammatory response. Inflammation, in the case of AD, does not take place in the

blood brain barrier but in the cells of the CNS [61]. Curcumin, with its anti-inflammatory

properties, effectively baulks inflammation engendered by activated microglia.

A study corroborated that nuclear factor kappa-light-chain-enhancer of activated B cell (NF-

kB) levels were exacerbated in patients with AD through the underlying action of βA4 protein (a

component of the Aβ plaques) deposition. NF-B is a transcription factor that actuates genes

related to inflammation by migrating into the nucleus. Curcumin blocks NF-B and hence

suppresses inflammation that would have occurred due to NF-B [62, 63].

Chemokines are part of cytokines that recruit leukocytes to inflammatory site. Aβ plaques

induce the upregulation of chemokine receptors in the cells of CNS. This culminates in CNS

cells being more sensitive to chemokine, thereby increasing inflammation [61]. Curcumin blocks

the release of pro-inflammatory cytokines, hence playing an important role in tackling the

inflammation caused in AD patients [64].

Antioxidant effects

Oxidative stress is a condition wherein the production of oxygen (mainly in form of ROS)

exceeds the rate at which one’s body is able to eliminate them. Oxidative stress leads to

aggregation of Aβ protein, further intensifying Aβ in the brains of AD patients [1]. Free radicals

(highly reactive molecules which have an unpaired electron) are formed by cellular metabolism

as well as high-energy radiations such as ultraviolet rays, nitrogen oxides, and metals. The

unpaired electrons in free radicals give rise to their high reactivity. In view of this, free radicals

cause oxidative damage to DNA, proteins, as well as lipids and are one of the touted reasons

behind several age-related degenerative diseases, inclusive of AD. Curcumin has an antioxidant

property. Antioxidants are compounds that forge free radicals [65]. The antioxidant property of

curcumin is due to the presence of polyphenols in its structure [39]. Moderate depolarization of

the inner membrane of mitochondria attenuates the production of ROS. Curcumin acts as an

uncoupler to depolarize the mitochondrial membrane and hence curtail oxidative stress [66]. In a

conducted research study, curcumin was discovered to inhibit the proliferation of free radicals

when a dose of 1mg/Kg was intravenously injected in mice. The results obtained from this study

showed diminished infarct volume, restrained oxidative stress and attenuation of water content in

the mice’s brain [67].

Peroxynitrite, a potent oxidant, attacks cellular components [68]. In AD pathogenesis,

peroxynitrite, which produces nitrotyrosine in neurons, has been evidenced to result in oxidative

damage of nerve cells. Immunoreactivity of nitrotyrosine in the cytoplasm of neurons in the

cerebral cortex was observed in neurodegenerated regions [69]. In a published study carried out

by Mythri et al., the authors conjectured that through direct detoxification, pretreatment of

curcumin could protect the mitochondrial brain in opposition to formation of in vitro

peroxynitrite, subsequently obviating the development of 3-nitrotyrosine. In the case of in vivo,

curcumin protects the mitochondrial brain through the aggrandizement of cellular glutathione

levels [70].

Metal chelation effect

According to the International Union of Pure and Applied Chemistry (IUPAC), chelation

refers to the formation of bonds between two or more separate binding sites within the same

ligand and a single central atom [71]. Metals are known to cause neurotoxicity in the brain [72].

A conducted study evidenced that copper increases beta sheets and alpha helices in Aβ protein.

To top it off, both copper and iron result in oxidative stress in the brain [73]. Lipid peroxidation

is brought about by the interaction of cadmium and iron with Aβ protein [74]. Lipid peroxidation

causes the generation of free radicals that increases oxidative stress in the brain. The interaction

of cadmium with Aβ protein was effectively curtailed by curcumin. Studies have suggested that

curcumin binds with metals like lead, cadmium, iron, and zinc, forming a metal-curcumin

complex and subsequently rendering them non-toxic [75].

Cholesterol lowering effect

Accumulations of cholesterol esters are potent precursors in the formation of Aβ plaques.

Cholesterol increases Aβ levels in the body [76]. Drugs that inhibited cholesterol synthesis were

found to reduce the synthesis of Aβ plaques in several animals such as rabbits, guinea pigs, and

transgenic mice [76]. The role of cholesterol in AD, however, remains a topic of debate among

scientists, since the exact mechanism underlying the effect of cholesterol in AD is yet to be

deciphered. Curcumin effectively pares cholesterol formation down [77]. With the curbing of the

production of lipid peroxides, curcumin could help reduce the amount of Aβ plaques in the brain.

Limitations and side effects of curcumin

With some of the benefits of curcumin relating to AD having been expounded, it is also

worth looking at some of the side effects. Curcumin not only adds taste to food but could also

make remarkable changes to the human body, thus paving way to multitudinous researches in the

medical field. However, there are always two sides of a coin.

In a recent published study, the author found curcumin to inhibit sperm motility and possibly

reduce testosterone levels through the hyperpolarization of the sperm plasma membrane as well

as curtailment of intracellular acidification [78]. To the very best of our knowledge, this is the

only published study that enunciates the side effect of curcumin.

Flavonoids participate in reducing Aβ plaques through assorted range of mechanisms [79].

However, there are insubstantial studies proving the efficiency of these mechanisms in vitro.

Also, there are certain drawbacks these mechanisms face in vivo. Bioavailability, generally, is

the proportion of administered drug that is absorbed in the bloodstream [80].

Flavonoids are in their glycosylated form when ingested. Suffice to say, they are not

subjected to any modifications in the stomach owing to their structures being unharmed until

reaching the small intestine [81]. Upon getting to the small intestine, and with the help of

enzymes such as B-galactosidase and lactase-phlorizin hydrolase, flavonoids are hydrolyzed [82].

Microorganisms present in the intestine also assist in this process [83]. Flavonoids undergo

conjugation following being absorbed. Conjugation involves methylation, sulfation, and

glucuronidation [84]. These processes take place with the criterion of detoxifying ingested

flavonoids and increase hydrophilicity of substrate, enabling them to be easily eliminated from

the body in the form of urine [85]. Additionally, flavonoids are not able to cross the blood brain

barrier, owing to its conjugated form being hydrophilic, thus its bioavailability is curtailed.As

flavonoids get metabolized, they lose some of their properties. Sulphated and o-methylated forms

of flavonoids have lower antioxidant properties as compared to their parent substance [86].

Poor bioavailability of curcumin could be tackled by the following means:

1. Using liposomal curcumin. Intravenous administration of liposomal curcumin (curcumin

loaded Human Serum Albumin nanoparticles) has been evidenced to induce remedial

effects without triggering toxicity [87];

2. Employing poly (lactic-co-glycolic acid) nanoparticles of curcumin (CUR-PLGA-NPs),

which has been evidenced to enhance bioavailability of curcmin [88];

3. Piperine, which when orally ingested with curcumin increases bioavailability of curcumin.

This property is owed to piperine’s ability to inhibit glucuronidation in the intestine and

liver. The effectiveness of piperine was evinced in both rats and humans [89].

Regarding metabolism, flavones and flavanones produce phenylpropionic acids. These acids

are further broken down to benzoic acids by bacteria. An increase in hippuric acid was observed

in humans following the ingestion of tea [90]. As far as curcumin is concerned, its major biliary

metabolites include glucuronides of tetrahydrocurcumin and hexahydrocurcumin in rats. More so,

dihydroferulic acid with traces of ferulic acid has been found to be minor biliary metabolites [91].

DIETARY SUPPLEMENTATION

There are ever growing number of dietary supplements and herbal remedies being marketed

as possible treatments to either delay or prevent AD and other memory related conditions. Most

of these products generally appear to be great options to the regular consumer based on the fact

that they either have high vitamin content or contain most natural ingredients. As rigorous

scientific research required by the US FDA for the approval of a prescription drug is not required

by law for the marketing of dietary supplements, effectiveness and safety of some of these

―medical foods‖ are somewhat questionable.

Omega-3 fatty acids

Omega-3s are a type of polyunsaturated fatty acids (PUFs) found in all body cells as a part of

the cell membrane, playing major roles in cell membrane fluidity, stability, and synaptic

connectivity. Postulation on fatty acid oxidation by free radicals resulting in cell membrane

damage and subsequently contributing to the pathogenesis of AD has been put forward.

Researchers have linked high intake of omega-3s to a possible reduction in risk of dementia or

cognitive decline [92, 93].

PUFs, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are the major

omega-3 fatty acids that have been studied in human clinical trials to date. They are responsible

for absorbing oxidative stress of free radicals and increasing cell membrane fluidity necessary

for lipid raft creation and formation of effective synaptic contacts. DHA, which is the most

abundant omega-3 fatty acid in the brain, is found in fatty membranes surrounding nerve cells,

especially at the cell junction [92, 94].

Regular consumption of omega-3 rich fish oil has been found to lower the incidence of AD in

epidemiological studies. It was also found that daily dietary supplementation with 900 mg DHA

produced 7-year age improvement in cognition over just 24 weeks as compared to placebo in

elderly patients with cognitive decline. However, patients who possessed apolipoprotein E

(ApoE) allele status failed to respond positively to omega-3 treatment. This could possibly be the

basis for future studies [94]. Research studies have also implied the effect of omega 3 fatty acids

might limit AD pathology by reducing amyloid formation, thus, minimizing aggregation into

plaques and increasing its clearance [95].

Diets high in saturated fat: caprylic acid and coconut oil

Caprylic acid is a medium-chain triglyceride (fat) produced by processed coconut oil or palm

kernel oil, and is an active ingredient of the ―medical food‖ Axona, which targets the nutritional

needs of AD patients [96]. Ketone bodies are produced when caprylic acid is metabolized in the

body. This is thought to provide an alternative energy source for impaired brain cells in AD

patients that have lost their ability to utilize glucose, which is the brain’s chief source of energy.

In a study, patients taking Axona displayed improvement in cognition when measured at 45 and

90 days of supplementation. However, benefits were only seen in ApoE4 negative patients and

were short lived. Axona was eventually discontinued due to its adverse side effects such as

diarrhea, flatulence, and dyspepsia [96].

Coconut oil is a less expensive source of caprylic acid and has been reported to help AD

patients. Definitive scientific and/or clinical evidences on the effectiveness of coconut oil for

either the prevention or treatment of AD are limited, as no clinical trial data, as of yet, is

available to substantiate or refute these claims [97, 98].

Ginkgo biloba

Ginkgo biloba, a Chinese herb, has been studied for its potential benefit in AD treatment. It

contains platelet activating factor antagonist, ginkgolide B, and has been used in stroke trials due

to this property. It is also thought to have both antioxidant and anti-inflammatory properties,

protecting cell membranes and regulating neurotransmitter function [99]. Ginkgo has been used

for centuries in traditional Chinese medicine and is currently being used in Europe to alleviate

cognitive symptoms associated with a number of neurological conditions. With that said, results

from a large-scale primary and secondary prevention study found no benefits of ginkgo biloba in

preventing the development or slowing mild cognitive impairment in AD. Researchers found no

statistical difference in rates of dementia or AD between the ginkgo and placebo groups. In spite

of this failure, ginkgo remains a popular treatment for a variety of medical conditions including

memory and cognitive deficits [99-101].

Huperzine A

Huperzine A, another Chinese herb, is a moss extract that has been used in traditional

Chinese medicine for centuries. Its pharmacological properties include being an

acetylcholinesterase inhibitor, which happens to be one class of FDA-approved AD medications

[102]. Laboratory experiments have demonstrated huperzine A to alter neuronal iron content in

animal models of AD, thus, reducing amyloid plaque formation and abrogating cell death.

Concurrently, a large scale clinical trial conducted by the Alzheimer’s Disease Cooperative

Study (ADCS) using huperzine A as a treatment for mild to moderate AD showed participants

having no greater benefits than those taking placebo [103].

Presently, available formulations of huperzine A are dietary supplements. These are

unregulated and manufactured with no uniform standards, which could increase the risk of

serious sides effects, especially if used in combination with FDA-approved AD drugs [104, 105].

Souvenaid

Souvenaid is a125-ml (125-kcal) once-daily drink that has now become available and used as

medical food in the treatment of AD under medical supervision [106, 107]. It combines a variety

of substrates, including uridine monophosphate, phospholipid, choline, and omega-3 fatty acids,

vitamins, and antioxidants, which are thought to be essential for formation of synaptic

membranes [106]. The AD brain has shown evidence of synaptic failure, and this is one of the

earliest manifestations of the disease [107]. The constituent of Souvenaid is expected to generate

new synaptic connections such as dendritic spine growth. Results from a clinical trial evinced

that patients receiving Souvenaid displayed significant improvement in verbal association testing

in comparison to the controlled group after 24 weeks [106]. Souvenaid is currently being highly

recommended as one of the leading supplements in AD treatment.

Vitamins C and E

Dietary supplements and vitamins containing folic acid and vitamin C have been shown to

have remarkable effects in the prevention of AD and improve memory loss, on the basis that

folic acid reduces homocysteine levels, and vitamin C, when combined with vitamin E, reduces

the risk of AD. Vitamin E should be taken in conjunction with vitamin C as a recharging

antioxidant that maximizes the dose of vitamin E. In addition to its effects in combination with

vitamin E, vitamin C has been widely studied for prevention and treatment of AD [30].

Vitamin C is an essential vitamin that cannot be produced by humans from glucose or other

substrates. Fortunately, dietary sources of vitamin C are common and include citrus fruits,

berries and numerous vegetables that are common part of most human diets globally. Several

epidemiologic and cohort studies have investigated the association of vitamin C dietary intake

and supplementation with AD and cognitive function in older adults. Recommendation on taking

at least 2000mg of vitamin C each day has been suggested [36, 108].

MEDITERRANEAN DIET

The Mediterranean diet (MeDi) is adapted from eating patterns seen in Italy, Spain, Greece,

and other Mediterranean countries. The diet involves high intake of legumes, olive oil, fruits,

nuts, vegetables, and cereals, moderate consumption of fish and wine, as well as low intake of

dairy products, red meat, processed meats, and sugars [109].

Investigations have shown adherence to MeDi to be associated with lower incidences of

stroke, type 2 diabetes, other cardiovascular diseases, and some cancers [110–112]. Research has

also indicated that greater adherence to MeDi is associated with reduced risk of developing

forms of dementia such as AD [9]. Nevertheless, some research studies have found no

association between the MeDi and risk of developing dementia [110]. The MeDi provides a

combination of nutrients that may proffer protection against cognitive decline. For example, the

diet is in rich mono-unsaturated fatty acids and fish, low in levels of saturated fat, high in levels

of antioxidants such as vitamin C, vitamin E, complex phenols, carotenoids, and flavonoids, as

well as high levels of vitamin B12 and folate [110, 113].

Oxidative stress plays a key role in the pathogenesis of AD. Postmortem AD studies in brain

tissues have revealed the presence of oxidized proteins, lipids, and DNA as a sign of oxidative

damage [114]. Further postmortem studies have also detected free radical attacks resulting in

mitochondrial and DNA damage, along with the presence of redox active metals in beta plaques

that produce free radicals [115]. Natural antioxidant defense systems include the action of three

main radical-scavenging enzymes: superoxide dismutase (SOD), catalase and glutathione-S-

transferase (GST). Moreover, the micronutrients vitamins A, C, and E, are richly provided

through the MeDi. These vitamins have been shown to have antioxidative properties. Similarly,

carotenoids and flavonoids are dietary antioxidants.

Several studies have illustrated antioxidants such as vitamins intake could be associated with

reduced incidence of dementia [116], and specifically reduced incidence of AD [117]. Zaidi and

Banu [118] conducted a study where they evaluated the efficacy of vitamins A, E, and C as

antioxidants individually and in combination with antioxidant systems in stressed rats. Their

results indicated that immobilization induced stress-produced ROS in the brain of the rats,

resulting in declined levels of SOD, catalase, and GST [118]. Consequently, ROS led to lipid

peroxidation, which was observed as an increase in thiobarbituric acid reactive substances [118].

Nonetheless, treatment with vitamins A, E, and C resulted in an increase in ROS-scavenging

enzymes SOD, GST, and catalase, as well as decrease in lipid peroxidation [118]. On top of that,

research findings have also suggested that vitamin intake from food sources are more effective

than those received via supplementation. In many studies, such as that of Petersen et al. [119]

and Devore et al. [117], it has been found that vitamin E and other antioxidants taken through

supplementation do not show improvement in AD symptoms [120]. Vitamin E from food sources,

such as that obtained from MeDi diet (nuts, vegetables, fruits) are in the form of tocopherols and

tocotrienols. As such, full range of vitamin E is consumed [120]. In contrast, vitamin E intake

from supplements provides only α-tocopherols. This has been shown to curtail serum

concentrations of γ- and δ-tocopherol [120]. The reduced range of vitamin E found in

supplementation might explain the reduced health benefits accompanying supplements in

comparison to natural vitamin E intake. Complex phenols and olive oil as well as carotenoids are

also antioxidants consumed in MeDi. Olive oil has been found to increase enzymes involved in

antioxidation, such as paraoxonase [121].

MeDi is also characterized by its lowfat intake, in which low proportions of consumed fats

are saturated fats, with higher proportions being mono-unsaturated fats. Olive oil is the major

source of fats in MeDi. Additionally, fish is another source of fat that provides low amounts of

saturated fat in comparison with poultry. The association between dietary fat intake and AD

development has been studied. Morris et al. found a 60% reduction in risk of developing AD

when n-3 polyunsaturated fatty acids and fish were consumed at least once a week, in

comparison to when they were rarely or never consumed. They also found that individuals

consuming increased saturated fats and trans-unsaturated fats showed increased risk of AD [122].

However, those consuming high intake of omega-6-polyunsaturated and monounsaturated fats

had a significantly lowered risk of AD [122].

Consumption of vegetable fats as well as high ratio of poly-unsaturated to saturated fats has

also been associated to reduced AD risk [122]. Studies have found a possible mechanism by

which poly- and mono-unsaturated fats reduce AD risk. Unsaturated fatty acids may be

protective due to its role in maintaining the integrity of neuronal membrane structures and in the

regulation of synaptic membranes and neuronal transmission [123, 124]. Rodents fed with

unsaturated fats were found to exhibit greater memory in comparison to rodents that were fed

with saturated fats [125]. A possible mechanism explaining the protective role of unsaturated fats

against AD involves the activation of protein kinase C (PKC) and the phosphorylation of protein

F1, which consequently results in increment in synaptic plasticity and memory storage [125]. It

was suggested that unsaturated fatty acids activate PKC, which leads to an increase in protein F1

phosphorylation, resulting in an increase in neurotransmitter release and growth at the

presynaptic terminal [125]. A second possible mechanism involves the activation of PKC, which

regulates ionic currents to assist neuronal patterns needed for learning [125]. It should be noted

that there are several subsets of PKC, each with its own specific substrate and activator. Hence,

more research into these mechanisms needs to be conducted with respect to the different PKC

subsets.

Inflammation and inflammatory mediators, also involved in the pathogenesis of AD, are

associated with cognitive decline [126, 127]. C-reactive protein (CRP) is an upregulated

inflammatory marker present in neuronal plaques and neurofibrillary tangles in the brains of AD

patients [128, 129]. However, increased adherence to MeDi has been connected to decline in

CRP levels in the brain [121, 130]. IL-6 cytokine is another inflammatory mediator that has been

associated with increased decline in cognitive functioning [131] together with increased risk of

dementia [132]. Adherence to MeDi diet has been found to significantly reduce levels of IL-6

[133] as well as curtail other inflammatory markers, such as white blood cell count [134]. Also,

genetic studies have revealed the polymorphism of the IL-6 gene, which results in a decrement in

IL-6 activity, is linked to delayed onset and reduced risk of developing AD [135].

Components of MeDi, such as extra virgin olive oil, wine, and carotenoids supplemented

through the diet,have been found to be associated with reduced IL-6 and thus, minimized

inflammation. Tyrosol and caffeic acid found in extra virgin oil and wine have been found to

reduce peripheral IL-6 levels in healthy participants [136]. RA is a subset of carotenoids and

retinoids. A derivative of RA has been found to cause reduction in both IL-6 and IL-1 levels with

several studies looking into its role as a therapeutic option for AD [137, 138]. RA has also been

found to relieve symptoms associated with olfactory dysfunction in AD patients [139–141]. In

addition to extra virgin olive oil providing anti-inflammatory components, Oleocanthal, a

phenylethanoid, has been postulated to have the potentiality of abating the risk of AD. The

results of Abuznait et al. [142] illustrated that Oleocanthal is in fact active in the clearance of Aβ

plaques and tau proteins, both of which are characteristic features in AD neuropathology [143].

SUMMARY AND FUTURE WORK

A plethora of research work has been and is still being conducted to elucidate the

complexities of AD pathology. Some mechanisms relating to AD, together with the connection

of the disease to other diseases as well as possible preventive mechanisms of AD, continue to be

untangled. Nonetheless, until effective treatments and preventative mechanisms are ascertained,

AD will continue to pose a great burden to aging people, especially those in Western Europe,

where the disease is thought to be prevalent.

The question that normally arises is ―Will AD ever be cured?‖ Indubitably. How? We do

believe by possibly employing a combination of therapeutics simultaneously. In view of this, we

intend to pursue this area of research in our future studies, where we would be looking into

applying some of the mentioned therapies above along with other therapeutics currently being

explored in an AD mouse model while monitoring domains of autophagy, inflammation, as well

as Aβ levels that are analogous to the disease.

ACKNOWLEDGMENTS

We are grateful to the National Natural Science Foundation of China, grant number

81671138, for funding this project. Additionally, we wish to acknowledge Ms. Wasan Adel

Abdulshaheed Ebrahim Ali Al-Ghasra for producing the images used in this report.

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/17-

0874r1).

REFERENCES

[1] Botchway BO, Iyer IC (2017) Alzheimer’s disease – the past, the present and the future. Sci J

Clin Med6, 1-19.

[2] Alzforum.org (2016) Lilliputian effect size fells phase 3 trial of solanezumab, leaving

its future uncertain. Available on http://www.alzforum.org/news/research-

news/lilliputian-effect-size-fells-phase-3-trial-solanezumab-leaving-its-future.

Accessed on May 9, 2017

[3] Harvey RA, Ferrier DR (2011) Ch. 15: Metabolism of dietary lipids; and Ch. 16: Fatty acid

and triacylglycerol metabolism. In Lippincott's Illustrated Reviews: Biochemistry,5th ed.

Wolters Kluwer, Philadelphia, pp. 173-180, 181-200.

[4] Trumbo P, Schlicker S, Yates AA, Poos M; Food and Nutrition Board of the Institute of

Medicine.The National Academies (2002) Dietary reference intakes for energy,

carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. J Am Diet

Assoc102, 1621-1630.

[5] Sakurai, M., Nakamura, K., Miura, K., Takamura, T., Yoshita, K., Nagasawa, S., ... &

Nakagawa, H. (2016). Dietary carbohydrate intake, presence of obesity and the incident risk of

type 2 diabetes in Japanese men. Journal of Diabetes Investigation7, 343-351.

[6] Xuan LT (2015) Effects of EXCESS fat intake. Available on

https://prezi.com/krar9krrla1x/effects-of-excess-fat-intake/, Accessed on May 8, 2017.

[7] Karantzoulis S, Galvin JE (2011) Distinguishing Alzheimer’s disease from other major forms

of dementia. Expert Rev Neurother11, 1579–1591.

[8] McBarron J (2012) Curcumin: The 21st Century Cure (2nd ed., p. 2). Kathleen Barnes, Brevard, NC.

[9] Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA (2006) Mediterranean diet and

risk for Alzheimer's disease.Ann Neurol59, 912-921.

[10] Lopes de Silva S, Vellas B, Elemans S, Luchsinger J, Kamphuis P, Yaffe K, Sijben J,

Groenendijk M, Stijnen T (2014) Plasma nutrient status of patients with Alzheimer's

disease: Systematic review and meta-analysis. Alzheimers Dement10, 485-502.

[11] Pagani L, Eckert A (2011) Amyloid-beta interaction with mitochondria. Int J Alzheimers Dis2011,

925050.

[12] Lee H, Casadesus G, Zhu X, Lee HG, Perry G, Smith MA, Gustaw-Rothenberg K, Lerner A

(2009) All-trans retinoic acid as a novel therapeutic strategy for Alzheimer's disease. Expert Rev

Neurother9, 1615-1621.

[13] Moneim AE (2015) Oxidant/antioxidant imbalance and the risk of Alzheimer's disease.Curr

Alzheimer Res 12, 335–349.

[14] Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM

(2008) Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a

mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J

Neurosci28, 11500-11510.

[15] Sun H, Kawaguchi R (2011) The membrane receptor for plasma retinol-binding protein, a new type

of cell-surface receptor. Int Rev Cell Mol Biol 288, 1–41.

[16] Carter CJ (2011) The fox and the rabbits—environmental variables and population genetics

(1) replication problems in association studies and the untapped power of GWAS (2)

vitamin A deficiency, herpes simplex reactivation and other causes of Alzheimer's

disease. ISRN Neurol2011, 394678.

[17] Goodman AB, Pardee AB (2003) Evidence for defective retinoid transport and function in late

onset Alzheimer's disease. Proc Natl Acad Sci U S A100, 2901–2905.

[18] Stough C, Simpson T, Lomas J, McPhee G, Billings C, Myers S, Oliver C, Downey LA (2014)

Reducing occupational stress with a B-vitamin focussed intervention: A randomized clinical

trial: Study protocol. Nutr J 13, 122.

[19] Maiese K, Chong ZZ, Hou J, Shang YC (2009) The vitamin nicotinamide: Translating nutrition into

clinical care. Molecules 14, 3446–3485.

[20] Liu D, Pitta M, Jiang H, Lee JH, Zhang G, Chen X, Kawamoto EM, Mattson MP (2013)

Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: Evidence for

improved neuronal bioenergetics and autophagy procession.Neurobiol Aging34, 1564–1580.

[21] Reynolds E (2006) Vitamin B12, folic acid, and the nervous system.Lancet Neurol5, 949–

960.

[22] Kennedy DO (2016) B vitamins and the brain: Mechanisms, dose and efficacy--areview.

Nutrients8, 68.

[23] Gillette-Guyonnet S, Secher M, Vella B (2013) Nutrition and neurodegeneration:

Epidemiological evidence and challenges for future research. Br J Clin Pharmacol 75,

738–755.

[24] Bhatti AB, Usman M, Ali F, Satti SA (2016) Vitamin supplementation as an adjuvant treatment for

Alzheimer’s disease. J Clin Diagn Res 10, OE07-OE11.

[25] Covarrubias-Pinto A, Moll P, Solis-Maldonado M, Acuña AI, Riveros A, Miro MP, Papic E,

Beltrán FA, Cepeda C, Concha II, Brauchi S, Castro MA (2015) Beyond the redox

imbalance: Oxidative stress contributes to an impaired GLUT3 modulation in

Huntington’s disease. Free Radic Biol Med89, 1085-1096.

[26] Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage:

Implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med14, 45–53.

[27] Bowman GL (2012) Ascorbic acid, cognitive function, and Alzheimer’s disease: A current

review and future direction. Biofactors38, 114-122.

[28] Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PH, Fried L, Kestenbaum

BR, Kuller LH, Langa KM, Lopez OL, Kos K, Soni M, Llewellyn DJ (2014) Vitamin D and the

risk of dementia and Alzheimer disease. Neurology83, 920–928.

[29] Darwish H, Zeinoun P, Ghusn H, Khoury B, Tamim H, Khoury SJ (2015) Serum 25-

hydroxyvitamin D predicts cognitive performance in adults. Neuropsychiatr Dis Treat11,

2217–2223.

[30] Annweiler C, Fantino B, Parot-Schinkel E, Thiery S, Gautier J, Beauchet O (2011)

Alzheimer’s disease—Input of vitamin D with memantine assay (AD-IDEA trial): Study

protocol for a randomized controlled trial. Trials 12, 230.

[31] Balion C, Griffith LE, Strifler L, Henderson M, Patterson C, Hecknman G, Llewellyn DJ, Raina P

(2012) Vitamin D, cognition, and dementia: A systematic review and meta-analysis.

Neurology79, 1397–1405.

[32] Banerjee A, Khemka VK, Ganguly A, Roy D, Ganguly U, Chakrabarti S (2015) Vitamin D

and Alzheimer's disease: Neurocognition to therapeutics. Int J Alzheimers Dis 2015,

192747.

[33] Reiter E, Jiang Q, Christen S (2007) Anti-inflammatory properties of α- and γ-tocopherol.

Mol Aspects Med 28, 668–691.

[34] Jiang Q. (2014). Natural forms of vitamin E: Metabolism, antioxidant, and anti-

inflammatory activities and their role in disease prevention and therapy. Free Radic Biol

Med 72, 76–90.

[35] Giraldo E, Lloret A, Fuchsberger T, Viña JA. (2014). Aβ and tau toxicities in Alzheimer's

are linked via oxidative stress-induced p38 activation: Protective role of vitamin E. Redox

Biol 2, 873–877.

[36] Grimm MO, Mett J, Hartmann T. (2016). The impact of vitamin E and other fat-soluble

vitamins on Alzheimer’s disease.Int J Mol Sci17, E1785.

[37] Kerela Agricultural University (2013) Processing & value addition.Available on

http://www.celkau.in/Crops/Spices/Turmeric/processing.aspx. Accessed on

February 8, 2017.

[38] Mary S. Easton. Curcumin. UCLA Alzheimer Translation Center.Available on

http://alzheimer.neurology.ucla.edu/Curcumin.html. Accessed on February 8, 2017.

[39] Basnet P, Skalkobasnet N. (2011). Curcumin: An anti-inflammatory molecule from a curry spice on

the path to cancer treatment. Molecules 16, 4567-4598.

[40] Ganguli M, Chandra V, Kamboh MI, Johnston JM, Dodge HH, Thelma BK, Juyal RC, Pandav R,

Belle SH, DeKosky ST (2000). Apolipoprotein E polymorphism and Alzheimer disease: The

Indo-US Cross-National Dementia Study. Arch Neurol57, 824-830.

[41] Santamaria I, Varghese M, Ksiȩżak-Reding H, Dzhun A, Wang J, Pasinetti GM (2012).

Paired helical filaments from Alzheimer disease brain induce intracellular accumulation

of tau protein in aggresomes. J Biol Chem287, 20522-20533.

[42] Sabogal-Guáqueta AM, Muñoz-Manco JI, Ramírez-Pineda JR, Lamprea-Rodriguez M,

Osorio E, Cardona-Gómez GP (2015). The flavonoid quercetin ameliorates Alzheimer's

disease pathology and protects cognitive and emotional function in aged triple transgenic

Alzheimer's disease model mice. Neuropharmacology 93, 134-145.

[43] Spencer JP (2007).The interactions of flavonoids within neuronal signalling

pathways.Genes Nutr2, 257-273.

[44] Mohebali N,ShahzadehFazeli SA, Ghafoori H, Farahmand Z, MohammadKhani E,

Vakhshiteh F, Ghamarian A, Farhangniya M, Sanati MH (2016). Effect of flavonoids rich

extract of Capparis spinosa on inflammatory involved genes in amyloid-beta peptide

injected rat model of Alzheimer's disease. Nutr Neurosci, doi:

10.1080/1028415X.2016.1238026.

[45] Yamakawa MY, Uchino K, Watanabe Y, Adachi T, Nakanishi M, Ichino H, Hongo K,

Mizobata T, Kobayashi S, Nakashima K, Kawata Y (2016)Anthocyanin suppresses the

toxicity of Aβ deposits through diversion of molecular forms in in vitro and in vivo

models of Alzheimer's disease. Nutr Neurosci 19, 32-42.

[46] Calò R, Marabini L (2014). Protective effect of Vaccinium myrtillus extract against UVA-

and UVB-induced damage in a human keratinocyte cell line (HaCaT cells).J Photochem

Photobiol B132, 27-35.

[47] Wang J, Ferruzzi MG, Ho L, Blount J, Janle EM, Gong B, Pan Y, Gowda GA, Raftery D,

Arrieta-Cruz I, Sharma V, Cooper B, Lobo J, Simon JE, Zhang C, Cheng A, Qian X, Ono

K, Teplow DB, Pavlides C, Dixon RA, Pasinetti GM (2012) Brain-targeted

proanthocyanidin metabolites for Alzheimer's disease treatment. J Neurosci32, 5144-

5150.

[48] Wang CN, Chi CW, Lin YL, Chen CF, Shiao YJ (2001) The neuroprotective effects of

phytoestrogens on amyloid beta protein-induced toxicity are mediated by abrogating the

activation of caspase cascade in rat cortical neurons. J Biol Chem 276, 5287-5295.

[49] Singh SK, Gaur R, Kumar A, Fatima R, Mishra L, Srikrishna S (2014) The flavonoid

derivative 2-(4' Benzyloxyphenyl)-3-hydroxy-chromen-4-one protects against Aβ42-

induced neurodegeneration in transgenic Drosophila: Insights from in silico and in vivo

studies. Neurotox Res 26, 331-350.

[50] Arispe N, Rojas E, Pollard HB (1993) Alzheimer disease amyloid beta protein forms

calcium channels in bilayer membranes: Blockade by tromethamine and

aluminum. Proc Natl Acad Sci U S A90, 567–571.

[51] Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R(2002)

Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin

receptor. J Neurosci22, RC221.

[52] Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM(2001) The curry spice

curcumin reduces oxidative damage and amyloid pathology in an Alzheimer

transgenic mouse. J Neurosci 21, 8370-8377.

[53] Champeau R (2009) Vitamin D, curcumin may help clear amyloid plaques found in

Alzheimer’s, Available on http://newsroom.ucla.edu/releases/ucla-study-finds-

vitamin-d-may-94903. Accessed on February 8, 2017.

[54] Chin D, Huebbe P, Pallauf K, Rimbach G (2013) Neuroprotective properties of curcumin in

Alzheimer's disease--merits and limitations.Curr Med Chem 20, 3955-3985.

[55] (2016) Types of WBCs. Boundless Anatomy and Physiology Boundless, from

https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-

textbook/cardiovascular-system-blood-17/white-blood-cells-166/types-of-wbcs-831-7902/

Accessed on May 27, 2016

[56] Olin M, Choi K, Molitor TW (2011) Morphine alters M. bovis infected microglia's ability to

activate γδ T lymphocytes.J Neuroimmune Pharmacol6, 578-584.

[57]Filiano AJ, Gadani SP, Kipnis J(2015) Interactions of innate and adaptive immunity in brain

development and function. Brain Res1617, 18–27.

[58] Zhang L, Fiala M, Cashman J, Sayre J, Espinosa A, Mahanian M, Zaghi J, Badmaev V,

Graves MC, Bernard G, Rosenthal M (2006) Curcuminoids enhance amyloid-beta

uptake by macrophages of Alzheimer's disease patients. J Alzheimers Dis.10, 1-7.

[59] (2017) Life extension update: Curcumin helps improve immune function.Life

Extension. Available on

http://www.lifeextension.com/newsletter/2012/5/curcumin-helps-improve-

immune-function/page-01. Accessed on February 8, 2017.

[60] Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH

(2009) Systemic inflammation and disease progression in Alzheimer

disease. Neurology73, 768-774.

[61] Xia MQ, Hyman BT (1999) Chemokines/chemokine receptors in the central nervous

system and Alzheimer's disease. J Neurovirol 5, 32-41.

[62] Singh S, Aggarwal BB. (1995). Activation of transcription factor NF-kappa B is

suppressed by curcumin (diferuloylmethane). J Biol Chem270, 24995-25000.

[63] Ida N, Hartmann T, Pantel J, Schröder J, Zerfass R, Förstl H, Sandbrink R, Masters

CL, Beyreuther K (1996) Analysis of heterogeneous A4 peptides in human

cerebrospinal fluid and blood by a newly developed sensitive western blot assay.

JBiol Chem271, 22908-22914.

[64] Sordillo PP, Helson L (2015) Curcumin suppression of cytokine release and

cytokine storm. A potential therapy for patients with Ebola and other severe viral

infections.In Vivo29, 1-4.

[65] Randhir R, Lin YT, Shetty K (2004) Stimulation of phenolics, antioxidant and

antimicrobial activities in dark germinated mung bean sprouts in response to

peptide and phytochemical elicitors. Process Biochem 39, 637–646.

[66] Zhu YG, Chen XC, Chen ZZ, Zeng YQ, Shi GB, Su YH, Peng X (2004) Curcumin

protects mitochondria from oxidative damage and attenuates apoptosis in cortical

neurons. Acta Pharmacol Sin 25, 1606-1612.

[67] Jiang J, Wang W, Sun YJ, Hu M, Li F, Zhu DY (2007) Neuroprotective effect of curcumin on focal

cerebral ischemic rats by preventing blood-brain barrier damage. Eur J Pharmacol561, 54-62.

[68] Olas B, Nowak P, Wachowicz B(2004) Resveratrol protects against peroxynitrite-

induced thiol oxidation in blood platelets. Cell Mol Biol Lett9, 577-587.

[69] Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread

peroxynitrite-mediated damage in Alzheimer’s disease.J Neurosci17, 2653-2657.

[70] Mythri RB, Jagatha B, Pradhan N, Andersen J, Bharath MM (2007) Mitochondrial complex

I inhibition in Parkinson's disease: How can curcumin protect mitochondria? Antioxid

Redox Signal9, 399-408.

[71] Muller P (1994) Glossary of terms used in physical organic chemistry. Pure Appl Chem66, 1077-

1184.

[72] Wright RO, Baccarelli A (2007) Metals and neurotoxicology.J Nutr 137, 2809-2813.

[73] Finkelstein DI, Lynch T, Wilkins S, Cherny RA, Bush AI (2010) Metals, oxidative stress

and brain biology. Encyclopedia of Stress,724-726. 10.1016/B978-012373947-6.00555-9.

Elsevier Science, Oxford.

[74] Rottkamp CA, Raina AK, Zhu X, Gaier E, Bush AI, Atwood CS, Chevion M, Perry G,

Smith MA (2001) Redox-active iron mediates amyloid-beta toxicity. Free Radic

Biol Med30, 447-450.

[75] Daniel S, Limson JL, Dairam A, Watkins GM, Daya S (2004) Through metal binding,

curcumin protects against lead- and cadmium-induced lipid peroxidation in rat

brain homogenates and against lead-induced tissue damage in rat brain. J Inorg

Biochem98, 266-275.

[76] Puglielli L, Tanzi RE, Kovacs DM. (2003). Alzheimer’s disease: The cholesterol connection. Nat

Neurosci6, 345-351.

[77] Soni KB, Kuttan R (1992) Effect of oral curcumin administration on serum peroxides

and cholesterol levels in human volunteers. Indian J Physiol Pharmacol 36, 273–

275.

[78] Naz RK (2014) The effect of curcumin on intracellular pH (pHi), membrane hyperpolarization and

sperm motility. J Reprod Infertil15, 62–70.

[79]Baptista FI, Henriques AG, Silva AM, Wiltfang J, da Cruz e Silva OA (2014) Flavonoids as

therapeutic compounds targeting key proteins involved in Alzheimer’s disease. ACS

Chem Neurosci5, 83–92.

[80] ―Bioavailability‖.Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and

Allied Health, Seventh Edition, 2003. Retrieved August 25, 2017 from http://medical-

dictionary.thefreedictionary.com/bioavailability

[81]Gee JM, DuPont MS, Rhodes MJ, Johnson IT (1998)Quercetin glucosides interact with the

intestinal glucose transport pathway. Free Radic Biol Med 25, 19-25.

[82] Day AJ, Cañada FJ, Díaz JC, Kroon PA, Mclauchlan R, Faulds CB, Plumb GW,

Morgan MR, Williamson G (2000) Dietary flavonoid and isoflavone glycosides are

hydrolysed by the lactase site of lactase phlorizin hydrolase.FEBS Lett468, 166-

170.

[83] Day AJ, DuPont MS, Ridley S, Rhodes M, Rhodes MJ, Morgan MR, Williamson G (1998)

Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and

liver beta-glucosidase activity. FEBS Lett436, 71-75.

[84] Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L (2004) Polyphenols: Food sources

and bioavailability. Am J Clin Nutr79, 727-747.

[85] Liu Z, Hu M (2007) Natural polyphenol disposition via coupled metabolic pathways.

Expert Opin Drug Metab Toxicol3, 389–406.

[86]Spencer JP, Schroeter H, Crossthwaithe AJ, Kuhnle G, Williams RJ, Rice-Evans C (2001)

Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen

peroxide-induced cell death in neurons and fibroblasts. Free Radic Biol Med 31, 1139-

1146.

[87] Kim TH, Jiang HH, Youn YS, Park CW, Tak KK, Lee S, Kim H, Jon S, Chen X, Lee KC.

(2011) Preparation and characterization of water-soluble albumin-bound curcumin

nanoparticles with improved antitumor activity. Int J Pharm 403, 285-291.

[88]Xie X, Tao Q, Zou Y, Zhang F, Guo M, Wang Y, Wang H, Zhou Q, Yu S (2011) PLGA

nanoparticles improve the oral bioavailability of curcumin in rats: Characterizations and

mechanisms. J Agric Food Chem59, 9280-9289.

[89]Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS (1998) Influence of piperine

on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med64,

353-356.

[90]Hollman PC (2004) Absorption, bioavailability, and metabolism of flavonoids.Pharm Biol42,

74-83.

[91]Holder GM, Plummer JL, Ryan AJ (1978)The metabolism and excretion of curcumin (1,7-

bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat.Xenobiotica 8,

761-768.

[92] Jicha GA, Carr SA (2010) Conceptual evolution in Alzheimer’s disease: Implications

for understanding the clinical phenotype of progressive neurodegenerative

disease. J Alzheimers Dis19, 253–272.

[93] Jicha GA, Markesbery WR (2010) Omega-3 fatty acids: Potential role in the management of

early Alzheimer’s disease. Clin IntervAging5, 45–61.

[94] Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin

JE, Emond J, Jack CR Jr, Weiner M, Shinto L, Aisen PS (2010)

Docosahexaenoic acid supplementation and cognitive decline in Alzheimer

disease: A randomized trial. JAMA304, 1903–1911.

[95] Arab L, Sabbagh MN (2010). Are certain lifestyle habits associated with lower

Alzheimer’s disease risk? J Alzheimers Dis20, 785–794.

[96] Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC (2009) Study of the

ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: A randomized,

double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond)6, 31.

[97] Van der Auwera I, Wera S, Van Leuven F, Henderson ST (2005) A ketogenic diet reduces

amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease. Nutr Metab (Lond) 2,

28.

[98] Kivipelto M, Rovio S, Ngandu T, Kåreholt I, Eskelinen M, Winblad B, Hachinski V,

Cedazo-Minguez A, Soininen H, Tuomilehto J, Nissinen A (2008) Apolipoprotein E

epsilon4 magnifies lifestyle risks for dementia: A population-based study. J Cell Mol

Med12, 2762–2771.

[99] DeKosky ST1, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA,

Lopez OL, Burke G, Carlson MC, Fried LP, Kuller LH, Robbins JA, Tracy RP,

Woolard NF, Dunn L, Snitz BE, Nahin RL, Furberg CD; Ginkgo Evaluation of

Memory (GEM) Study Investigators (2008) Ginkgo biloba for prevention of

dementia: A randomized controlled trial. JAMA300, 2253–2262.

[100] Snitz BE, O'Meara ES, Carlson MC, Arnold AM, Ives DG, Rapp SR, Saxton J, Lopez OL,

Dunn LO, Sink KM, DeKosky ST; Ginkgo Evaluation of Memory (GEM) Study

Investigators (2009) Ginkgo biloba for preventing cognitive decline in older adults: A

randomized trial. JAMA302, 2663–2670.

[101] Oken BS, Storzbach DM, Kaye JA (1998) The efficacy of Ginkgo biloba on

cognitive function in Alzheimer disease. Arch Neurol55, 1409-1415.

[102] Yang G, Wang Y, Tian J, Liu JP (2013) Huperzine A for Alzheimer’s disease: A

systematic review and meta-analysis of randomized clinical trials. PLoS One8, e74916.

[103] Zhang Z, Wang X, Chen Q, Shu L, Wang J, Shan G (2002) [Clinical efficacy and

safety of huperzine Alpha in treatment of mild to moderate Alzheimer disease, a

placebo-controlled, double-blind, randomized trial]. Zhonghua Yi Xue Za Zhi82,

941-944.

[104] Rafii MS, Walsh S, Little JT, Behan K, Reynolds B, Ward C, Jin S, Thomas R,

Aisen PS; Alzheimer's Disease Cooperative Study (2011) A phase II trial of

huperzine A in mild to moderate Alzheimer disease. Neurology76, 1389–1394.

[105] Li J, Wu HM, Zhou RL, Liu GJ, Dong BR (2008) Huperzine A for Alzheimer’s

disease. Cochrane Database Syst Rev2, CD005592.

[106] Thaipisuttikul P, Galvin JE (2012) Use of medical foods and nutritional approaches

in the treatment of Alzheimer’s disease. Clin Pract (Lond)9, 199–209.

[107] Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological

alterations in Alzheimer disease. Cold Spring Harb Perspect Med1, A006189.

[108] Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S,

Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Trapp G,

Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR,

Zachariah S, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C,

Monnell KA, Gordon K, Tomaska J, Segal Y, Peduzzi PN, Guarino PD (2014) Effect of

vitamin E and memantine on functional decline in Alzheimer disease: The TEAM-AD

VA cooperative randomized trial. JAMA311, 33–44,

[109] Willett WC, Sacks F, Trichopoulou A, Drescher G, Ferro-Luzzi A, Helsing E, Trichopoulos D

(1995) Mediterranean diet pyramid: A cultural model for healthy eating. Am J Clin Nutr61,

1402S-1406S.

[110] Pauwels EK (2011) The protective effect of the Mediterranean diet: Focus on cancer and

cardiovascular risk.Med Princ Pract20, 103-111.

[111] Liyanage T, Ninomiya T, Wang A, Neal B, Jun M, Wong MG, Jardine M, Hillis GS, Perkovic V

(2016) Effects of the Mediterranean diet on cardiovascular outcomes-a systematic review and

meta-analysis.PLoS One11, e0159252.

[112] Berrino F (2016) Mediterranean diet and its association with reduced invasive breast cancer

risk.JAMA Oncol2, 535-536.

[113] Byers T, Perry G (1992) Dietary carotenes, vitamin C, and vitamin E as protective antioxidants in

human cancers.Annu RevNutr12, 139-159.

[114] Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, Li L (2004) Oxidative

modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with

idiopathic Parkinson’s and Alzheimer’s diseases.J Biol Chem279, 13256–13264.

[115] Mariani E, Polidori MC, Cherubini A, Mecocci P (2005) Oxidative stress in brain aging,

neurodegenerative and vascular diseases: An overview.J Chromatogr B Analyt Technol Biomed

Life Sci827, 65–75.

[116] Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS, Aggarwal NT, Scherr PA (2005)

Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change.Am J

Clin Nutr81, 508-514.

[117] Devore EE, Grodstein F, van Rooij FJ, Hofman A, Stampfer MF, Witteman JC, Breteler MM

(2010) Dietary antioxidants and long-term risk of dementia.Arch Neurol67, 819-825.

[118] Zaidi SM, Banu N (2004) Antioxidant potential of vitamins A, E and C in modulating oxidative

stress in rat brain.Clin Chim Acta340, 229-233.

[119] Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J,

Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ; Alzheimer's Disease Cooperative Study

Group (2005)Vitamin E and donepezil for the treatment of mild cognitive impairment.N Engl J

Med352, 2379–2388.

[120] Huang HY, Appel LJ (2003) Supplementation of diets with alpha-tocopherol reduces serum

concentrations of gamma- and delta-tocopherol in humans.J Nutr133, 3137-3140.

[121] Blum S, Aviram M, Ben-Amotz A, Levy Y (2006) Effect of a Mediterranean meal on postprandial

carotenoids, paraoxonase activity and C-reactive protein levels.Ann Nutr Metab50, 20-24.

[122] Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Schneider J, Wilson

RS (2003) Dietary fats and the risk of incident Alzheimer disease.Arch Neurol60, 194-200.

[123] Panza F, Solfrizzi V, Colacicco AM, D'Introno A, Capurso C, Torres F, Del Parigi A, Capurso S,

Capurso A (2004) Mediterranean diet and cognitive decline.Public Health Nutr7, 959–963.

[124] Solfrizzi V, Panza F, Capurso A (2003) The role of diet in cognitive decline. J Neural Transm

(Vienna)110, 95–110.

[125] Wong KL, Murakami K, Routtenberg A (1989) Dietary cis-fatty acids that increase protein

F1 phosphorylation enhance spatial memory. Brain Res505, 302-305.

[126] Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P,

Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G,

Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman

C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL,

Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation

and Alzheimer's disease. Neurobiol Aging21, 383–421.

[127]Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harrris T, Shorr RI, Tylavsky FA, Newman AB

(2004) The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA292, 2237-

2242.

[128] Duong T, Nikolaeva M, ActonPJ. (1997). C-reactive protein-like immunoreactivity in the

neurofibrillary tangles of Alzheimer's disease. Brain Res749, 152-156.

[129]Wood JA, Wood PL, Ryan R, Graff-Radford NR, Pilapil C, Robitaille Y, Quirion R (1993)

Cytokine indices in Alzheimer's temporal cortex: No changes in mature IL-1 beta or IL-1RA but

increases in the associated acute phase proteins IL-6, alpha 2-macroglobulin and C-reactive

protein. Brain Res629, 245-252.

[130] Fung TT, McCullough ML, Newby PK, Manson JE, Meigs JB, Rifai N, Willet WC, Hu FB (2005)

Diet-quality scores and plasma concentrations of markers of inflammation and endothelial

dysfunction. Am J Clin Nutr82, 163–173.

[131] Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE (2002) Interleukin-6 and risk

of cognitive decline: MacArthur studies of successful aging. Neurology59, 371- 378.

[132] Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, Van Swieten JC, Stijnen T,

Hofman A, Witteman JC, Breteler MM (2004) Inflammatory proteins in plasma and the risk of

dementia: The Rotterdam Study.Arch Neurol61, 668-672.

[133] Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, D’Armiento M,

D’Andrea F, Giugliano D (2004) Effect of a Mediterranean-style diet on endothelial dysfunction

and markers of vascular inflammation in the metabolic syndrome: A randomized trial. JAMA292,

1440-1446.

[134] Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C (2004) Adherence to the

Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The

ATTICA Study. J Am Coll Cardiol44, 152–158.

[135] Papassotiropoulos A, Bagli M, Jessen F, Bayer TA, Maier W, Rao ML, Heun R (1999) A genetic

variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk

for sporadic Alzheimer's disease.Ann Neurol45, 666–668.

[136] Bertelli AA, Migliori M, Panichi V, Longoni B, Origlia N, Ferretti A, Cuttano GM,

Giovannini L(2002) Oxidative stress and inflammatory reaction modulation by

white wine. Ann NY Acad Sci957, 295–301.

[137] Shudo K, Nakagomi M, Yamagata N, Fukasawa H. (2009). Towards retinoid therapy for

Alzheimer’s disease.Curr. Alzheimer Res. 6, 302–311.

[138] Kagechika H, Kawachi E, Fukasawa H, Saito G, Iwanami N, Umemiya H, Hashimoto Y,

Shudo K (1997) Inhibition of IL-1-induced IL-6 production by synthetic

retinoids.BiochemBiophys Res Commun231, 243–248.

[139] Rawson NE, LaMantia AS (2006) Once and again: Retinoic acid signaling in the developing and

regenerating olfactory pathway. J Neurobiol66, 653–676.

[140] Rawson NE, LaMantia AS (2007) A speculative essay on retinoic acid regulation of neural stem

cells in the developing and aging olfactory system.Exp Gerontol42, 46–53.

[141] Doty RL (2008) The olfactory vector hypothesis of neurodegenerative disease: Is it

viable? Ann Neurol63, 7–15.

[142] Abuznait AH, Qosa H, Busnena BA, El Sayed KA, Kaddoumi A (2013) Olive-oil-derived

oleocanthal enhances β-amyloid clearance as a potential neuroprotective mechanism against

Alzheimer’s disease: In vitro and in vivo studies. ACS Chem Neurosci4, 973–982.

[143] Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: Progress and problems

on the road to therapeutics. Science297, 353-356.

[144] Remya C, Dileep KV, Tintu I, Variyar EJ, Sadasivan C (2014) Flavanone glycosides as

acetylcholinesterase inhibitors: Computational and experimental evidence. Indian J

Pharm Sci76, 567–570.

[145] Kanaze FI, Bounartzi MI, Georgarakis M, Niopas I (2007) Pharmacokinetics of the citrus

flavanone aglycones hesperetin and naringenin after single oral administration in human

subjects.Eur J Clin Nutr61, 472-477.

[146] Spencer JP (2008) Flavonoids: Modulators of brain function? Br J Nutr99, ES60-

ES77.

[147] Williams RJ, Spencer JP, Rice-Evans C (2004) Flavonoids: Antioxidants or signalling

molecules? Free Radic Biol Med36, 838-849.

[148]Graefe EU, Wittig J, Mueller S, Riethling A, Uehleke B, Drewelow B, Pforte H, Jacobasch

G, Derendorf H, Veit M (2001) Pharmacokinetics and bioavailability of quercetin

glycosides in humans. J Clin Pharmacol 41, 492-499.

[149] Wang L, Matsushita K, Araki I, Takeda M (2002) Inhibition of c-Jun N-terminal kinase

ameliorates apoptosis induced by hydrogen peroxide in the kidney tubule epithelial cells

(NRK-52E). Nephron 91, 142-147.

[150] Chang YL, Chen CL, Kuo CL, Chen BC, You JS (2010) Glycyrrhetinic acid inhibits

ICAM-1 expression via blocking JNK and NF-kappaB pathways in TNF-alpha-activated

endothelial cells. Acta Pharmacol Sin31, 546–553.

[151] Shah SA, Yoon GH, Kim MO (2015) Protection of the developing brain with anthocyanins

against ethanol-induced oxidative stress and neurodegeneration. Mol Neurobiol 51,

1278–1291.

[152] Bub A, Watzl B, Heeb D, Rechkemmer G, Briviba K (2001)Malvidin-3-glucoside

bioavailability in humans after ingestion of red wine, dealcoholized red wine and red

grape juice.Eur J Nutr 40, 113-120.

[153]Kano M, Takayanagi T, Harada K, Sawada S, Ishikawa F (2006) Bioavailability of

isoflavones after ingestion of soy beverages in healthy adults. J Nutr136, 2291–2296.

[154] Chang SKC (2002) Isoflavones from soybeans and soy foods. In: Functional foods:

biochemical & processing aspects, Vol. 2, Shi J, Mazza G, Le Maguer M, eds. CRC

Press, Boca Raton.

Fig. 1. Some food sources of vitamins A–E

Fig. 2. A picture of Curcumina longa

Fig. 3. Chemical structure of commercial curcumin

Fig. 4.The role of curcumin in AD.

Fig. 5. An illustration of a typical Mediterranean diet

Table 1. Mechanism, bioavailability and food sources of some flavonoids

Flavonoid Mechanism Bioavailability

(plasma concentration)

Dietary sources

Flavanones Inhibition of

acetylcholinesterase [144]

7.4mM for 135 mg of

flavanone ingested [145]

Orange juice

Grapefruit juice

Lemon juice [84]

Flavonols

Hampering of iNOS and

cyclooxygenase-2 expression;

Inhibition of NO production;

Hindering of cytokine release;

Impediment of NADPH oxidase

activation and subsequent reactive

oxygen species generation in

astrocytes and microglia.

Flavonols work by modulating

protein and lipid kinase signaling

pathways. By these mechanisms

flavanols reduce inflammation of

astrocytes and microglia [43, 146,

147]

7.0mM for 100 mg of

flavonol ingested [148]

Yellow onion

Curly kale

Leek

Cherry tomato

Broccoli

Tomato

Apple

Black tea infusion

Green tea infusion

Black grape

Blueberry [84]

Flavones

Inhibition of apoptosis of

neurons induced by

hydrogen and TNF-α [149,

150]

Unknown

Parsley

Celery

Capsicum pepper

[84]

Anthocyanidins

Attenuation of phospho-

nuclear factor kappa B and

cyclooxygenase 2, thus

curtailing inflammation and

oxidative stress [151]

0.003mM for 117 mg of

anthocyanin ingested

[152]

Aubergine

Black berry

Black currant

Blueberry

Black grape

Cherry

Rhubarb

Strawberry

Red wine

Red cabbage

Plum [84]

Isoflavonoids Same as flavonols

0.41mM for 102 mg of

isoflavonoids ingested

[153]

Soy cheese

Soy

Soy bean

Tofu [154]