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Nutritional Supplementation in Alzheimers disease.

Background

Alzheimer's disease (AD), also referred to as simply Alzheimer's, is a progressive brain disease that accounts for 60-70% of all cases of dementia. (1) Alzheimer's, whose symptoms manifest at around age 65, destroys an individual's thinking ability and memory, eventually impacting on cognitive functioning, including the ability to carry out simple tasks. Alzheimer's progresses from a mild condition which can only involve memory problems. As the disease worsens, the memory loss and other cognitive impairments become more apparent. Victims may have trouble finding their way back home or paying bills, in addition to change in mood or personality. The moderate stage of the disease is marked by damage to brain areas that control reasoning, sensory processing, conscious thought, and language. Confusion and loss of memory gets worse to the point that affected persons begin to have problems recognizing their friends and family. Besides having trouble learning new things and accomplishing tasks that involve multiple steps, individuals with moderate Alzheimer's may experience paranoia, hallucinations, and delusions. The severe stage of the disease is marked by the spread of tangles and plaques throughout the brain tissue, causing shrinkage. At this point, affected individuals cannot communicate and rely on other people for all aspects of care. As the end nears, the person tends to remain in bed all the time as the body shuts.

Causes of Alzheimer's

Despite decades of research, the causes of Alzheimer's are yet to be fully understood. It is however clear that there is an interplay between genetic and environmental factors. The disease develops out of a series of complex events that take place in the brain over an extended period of time. Up to 70% of AD risk can be attributed to genetics, while environmental factors and human lifestyle patterns account for the remaining 30% (Yegambaram, Manivannan, Beach, & Halden, 2015). (2)

Genetic factors

Genetic factors are thought to play a significant role in the early-onset Alzheimer's disease, a rare form of the condition that affect people along family lines. The familial AD is thought to occur due to one of the three different mutations that result in the formation of abnormal proteins. Single gene mutations on chromosome 1, 14, and 21, result in the formation of abnormal protein that could have a role in AD development. Mutations in chromosome 21 results in the formation of an abnormal amyloid precursor protein (APP) (Holocomb, et al., 1998). (3) While mutations in chromosomes 1 and 14 result in the formation of abnormal presenilin 1 and presenilin 2, respectively. Scientific investigation is still ongoing for the more common, late-onset Alzheimer's. Thus far, the apolipoprotein E (ApoE) gene has successfully been linked to the late onset AD (Corder, et al., 1993). (4) A study conducted by Corder et al. (1993) showed that both late familial onset and sporadic form of AD were associated with apolipoprotein E type 4 allele (APOE-epsilon 4). According to the findings of the study, an number of APOE-esilon 4 alleles in 42 families with late onset AD increased AD risk from 20% to 90%, while the mean age at onset decreased from 84 to 68 years. However, several other gene combinations are still suspected as a very small fraction of people carry APOE in the form that increases risk for the late-onset AD. APOE testing is currently used in research to study subjects who may be at an increased risk of developing AD. Though blood tests easily determine the APOE alleles an individual has, the findings cannot be used to predict the likelihood of an individual developing the condition (Corder, et al., 1993). (5)

Environmental factors

Many scientific investigations have been conducted in bid to understand the environmental factors that play a role in the development of AD or which trigger AD in individuals who are genetically susceptible. A review conducted by Gautrin and Gauthers (1989) on published reports on various environmental factors that could be playing a role in AD, including viruses, neurotoxic metals, aluminum, biological and immune system neurotoxins, and trace elements, suggested that multiple environmental factors play a significant role in the etiology of AD. A complex interaction between genetic susceptibility, environmental factors, and the aging process, and pathological alterations of the immune system were also seen as contributing factors to AD (Gautrin & Gauthers, 1989). (6) A review conducted by Yegambaram et al. (2015) established that long-term exposure to environmental contaminants such as organic and inorganic hazards, toxic metals, pesticides (organochlorine and organophosphate insecticides), air pollutants, and industrial chemicals, could have a role in neuro-inflammation and neuropathology that paves the way for AD development. (7) Even though several in vitro animal studies have provided evidence on how environmental contaminants alter metabolism and pathways associated with AD, data on epidemiologic association is still limited and, therefore, requires further research (Yegambaram, Manivannan, Beach, & Halden, 2015). (8)

Nutritional Supplementation and Alzheimer's disease

Even though knowledge on modifiable risk factors for AD remains limited, there is growing evidence of dietary risk factors in the development of the disease and age-related cognitive decline. Of interest are nutrients rich in antioxidants, dietary fats, B-vitamins, and fish. A review conducted by Morris (2009) pointed at the findings of several laboratory studies which show that antioxidant nutrients can protect the brain against inflammatory damage. (9) Substantial epidemiological evidence collected recently shows that omega-3 fatty acids, including docosahexaenoic acid could play a protective role in AD. In general, there is increasing evidence from epidemiological studies which suggest a relationship between AD and nutrition (Morris, 2009). (10) Much of the epidemiologic data available on the role of nutrition in AD report on potential metabolic derangements that could occur as a result of dietary insufficiency or excesses, and which can be corrected by dietary modification or supplementation. In addition to antioxidants and omega 3 fatty acids, nutritional supplements usually contain several other health promoting constituents such as flavonoids, trace minerals, and vitamins (Swaminathan & Jicha, 2014). (11) Through various mechanisms targeting the aging process, cellular health and regeneration, these nutrients may disrupt the pathogenic pathways involved in the development of AD and other chronic diseases (Swaminathan & Jicha, 2014). (12) Nutritional interventions are also found to be cost effective, generally safe, and socially acceptable, and easy to implement. While a lot has been studied in regard to nutritional intervention in AD, there still so much to be done before successful agents or combination of agents that offer specific treatment or prevention of AD are identified.

One of the areas with increased research activity concerns the efficacy of nutritional modifications in delaying behavioral/mood difficulties or cognitive decline experienced in Alzheimer's. Though several studies that have investigated benefits of individual supplements of vitamins show little or no benefit, findings from combinational formulations show improvements in cognitive performance and a wide range of behavioral difficulties associated with AD. A review conducted by Shea and Remington (2015) reported that an optimal nutritional approach to Alzheimer's might necessitate an early, multi-component nutritional approaches, including a Mediterranean-style diet, key combinational supplements, multivitamins. (13) This should be in conjunction with lifestyle modifications such as mental and physical exercise, social activity, and addition of pharmacological agents (Shea & Remingtpn, 2015). (14) A number of studies have reported on the impact of nutritional intervention on cognitive performance and behavioral difficulties experienced in Alzheimer's disease.

Dietary formulations

Some dietary formulations that could be beneficial in AD include the following:

Mediterranean Diet

The Mediterranean diet, basically composed of fresh vegetables and fruits, fish, and grains has been shown to play a protective role in the development of a number of chronic diseases, and particularly neurodegenerative diseases. While most previous research on the association between AD and diet focused on individual components in diet, recent findings show that composite dietary formulations such as the Mediterranean diet (MeDi) may offer a beneficial effect on the disease. A study conducted by Scarmeas et al. (2006) investigated the association between Mediterranean diet and the risk for AD. (15) During the study, 2,258 non-demented community-based individuals in New York were subjected to prospective analysis every 1.5 years. Adherence to Mediterranean diet, measured using a 0-9 point scale, was used as the main predictor in models who were adjusted for cohort, sex, ethnicity, age, apolipoprotein E genotype, education, smoking, calorie intake, medical comorbidity index, and body mass index (Scarmeas, Yaakov, Tang, Mayeux, & Luchsinger, 2006). (16) During the follow up course of 4 ([+ or -]3.0; range, 0.2-13.9) 262 incidents of AD were identified. The findings of the study showed that individuals who showed a higher adherence to Mediterranean diet had a lower risk for AD. It was hence concluded that a higher adherence to Mediterranean Diet is associated with a reduced AD risk (Scarmeas, Yaakov, Tang, Mayeux, & Luchsinger, 2006). (17) The positive effects of Mediterranean diet on AD have been corroborated by other studies. For instance, a study conducted by Morris et al. (2015) investigated whether MIND, a hybrid Mediterranean dietary approach aimed at stopping hypertension had an effect on the prevalence of AD. (18) The association was investigated in a prospective sample that included 923 participants, aged between 58 and 98 years. The findings of the study showed that a high and moderate adherence to MIND diet may reduce the risk of AD (Morris, et al., 2015). (19)

Nutraceutical Formulation

A study conducted by Remington et al. (2015) sought to establish whether nutritional intervention could have a positive impact on cognitive performance and behavioral difficulties experienced by people diagnosed with Alzheimer's. (20) During the double blind, multi-site, phase ii study, 106 individuals with AD were randomly selected for nutraceutical formulation (NF; folate, alphatocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for a period of 3 or 6 months, which was followed by an open-label extension during which subjects were provided with NF for 6 more months (Remington, et al., 2015). (21) The results of the study showed an improvement in the NF cohort compared to the placebo within three months and, it was therefore, concluded that NF improved or maintained cognitive performance and behavior/mood in AD patients. Nutraceutical diet has also been proposed to play a role in preventing abnormal epigenetic regulation, a key player in several pathological conditions including AD. Though numerous studies have investigated the role played by diet in modifying epigenetic patterns, there are very few studies that report on the role played by specific food components. Generally, bioactive food may modify some epigenetic mechanisms involved in AD (Davinelli, Calabrese, Zella, & Scapagni, 2014). (22)

Groups of Compounds/Nutrients

Antioxidants, flavonoids/flavonols, and polyphenols are some of the widely investigated groups of compounds investigated in AD.

Antioxidants in general

The progression of AD which is characterized by progressive loss of memory, reasoning and other cognitive skills has partly been thought to occur due oxidative/nitrosative stress, antioxidant decrease, and mitochondrial damage (Domenico, Barone, Perluigi, & Butterfield, 2015). (23) Over the years, several strategies have been proposed in the effort to reduce pro-oxidant species to ameliorate Alzheimer's pathology (Domenico, Barone, Perluigi, & Butterfield, 2015). (24) Evidence from recent in vivo and in vitro studies have suggested approaches that could be used in the removal of oxidant species in respect to AD. Several antioxidants have been investigated including N-acetyl-I-cysteine, vitamin D, ferulic acid, vitamin E, selenium, tricyclodecan-9-yl-xanthogenate, and melatonin. The use of multi-targeted approaches through formulas that combine more than one antioxidant compound has been suggested.

Flavonoids

Flavonoids are phenolic substances isolated fromnumerous species of vascular plants. There are more than 8000 individual compounds that can currently be categorized as flavonoids. In plants, flavonoids act as antioxidants, antimicrobials, visual attractors, photoreceptors, feeding repellants, and for light screening purposes. Over the years, findings from several studies have suggested that flavonoids have the capacity to influence a number of biological activities such as antiallergenic, vasodilation, antiviral, and anti-inflammatory actions. However, much of the research interest has been devoted to the understanding of the antioxidant activity of the flavonoids. The capacity of flavonoids to reduce free radicals in vitro has been subjected to many investigations, and important information on the relationships have so far been published. The limited knowledge on the uptake of flavonoids in humans has led to poor understanding on their in vivo efficacy. Most of the flavonoids consumed in human diets are converted to various phenolic acids, some of which continue to exhibit antioxidant properties (Pietta, 2000). (25) It's on this basis that some studies have suggested improvements in AD condition could be realized as a result of flavonoid intake. Flavonoids are sourced from a wide range of foods including plant and animal foods. However, vegetables and fruits are far richer sources of flavonoids compared to animal foods. Several studies provide evidence to show that flavonoids could be beneficial in AD.

As discussed in previous sections, there is increased scientific evidence that indicate elevation of the [beta]-amyloid (A[beta]) peptides to be a key factor in the pathogenesis of AD. According to Onozuka et al. (2008), nobiletin, a polymethoxylated flavone from citrus peels, improves cAMP/protein kinase A/extraceullar signal-regulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates A[beta]-induced memory impairment in AD model rats. (26) According to the researchers, the natural compound has the ability to improve memory deficit in amyloid precursor protein (APP) transgenic mice that express the human APP695 which harbor the double Swedish and London mutations. Using enzyme-linked immunosorbent assay (ELISA) the researchers showed that the quantity of guanidine-soluble A[beta]-40 and A[beta]-42 was greatly reduced in the brain following nobiletin administration to transgenic mice for 4 months (Onozuka, et al., 2008). (27) The findings of the study produced strong evidence that the natural compound had the potential to be a novel drug for AD treatment.

Polyphenols

Polyphenols are regarded to be the most abundant antioxidants in diet. Antioxidant polyphenols are present in a wide variety of dietary sources, such as fruits, vegetables, beverages, and a several plant and herbal extracts. Despite their widespread distribution, research on their human health benefits only started in mid 1990s. Currently, there is an increased interest in phenolic compounds due to the huge epidemiological evidence that suggest a relationship between consumption of polyphenols and resistance to certain chronic conditions such as cardiovascular diseases and cancer (Singh, Arseneault, Sanderson, Murthy, & Ramassamy, 2008). (28)

A review conducted by Rossi et al. (2008) investigated the benefits from dietary polyphenols for brain aging and AD. (29) According to the review, brain aging and neurodegenerative diseases of the elderly usually show impairment in redox metal homeostasis and oxidative damage. However, food polyphenols have the ability to counter the alterations in vitro, and, therefore, suggested to have the potential to function as anti-aging and neuroprotective agents. In spite of the increased evidence from in vitro studies that are trying to determine the mechanisms of action of dietary polyphenols, research in this field is still in the early stages and things like biotransformation, bioavailability, synergism, mechanisms of their antioxidant activity, and risk are not yet understood (Rossi, Mazzitelli, Arciello, Capo, & Rotilio, 2008). (30) Perhaps one of the studies that provided crucial evidence on the importance of polyphenols in AD was the Kame project conducted by Dai et al. (2006), and which investigated the effect of fruit and vegetable juices in AD. (31) The study was conducted against the background of growing evidence that suggests oxidative damage caused by the [beta]-amyloid peptide in the pathogenesis of AD may be hydrogen peroxide mediated, a compound that many polyphenols possess strong protection against. The researchers tested whether consumption of fruit vegetable juices, containing a high concentration of polyphenols, decreases the risk of incident probable AD (Dai, Borenstein, Wu, Jackson, & Larson, 2006). (32) The Kame project cohort comprised 1836 Japanese Americans residing in King County, Washington, and who were found to be dementia-free at baseline (1992-1994) and were followed through to 2001. After adjusting for potential confounders, the findings of the study showed that the hazard ratio for probable AD was 0.24 in subjects who drunk juices at least 3 times a day, and 0.84 for those who drunk the juices less often than once a week (Dai, Borenstein, Wu, Jackson, & Larson, 2006). (33) The inverse association was found to be more pronounced in subjects who possessed apolipoprotein E[epsilon]-4 allele those who had little physical activity. The study did not establish any association between dietary intake of vitamins C, E, and beta carotene or tea consumption (Dai, Borenstein, Wu, Jackson, & Larson, 2006). (34) The findings of the study provided evidence that fruit and vegetable juices may play a crucial role in delaying the onset of AD, especially among individuals with a high risk.

Specific Compounds/Nutrients

Research has focused on a number of specific compounds because of their promising status as probable agents for AD therapy. Considerable evidence exists against the following:

Omega -3 fatty acids

The critical role of omega fatty acids, also referred to as polyunsaturated fatty acids (PUFAs) in the cognitive function of an individual is well known. However, few studies report on the effects of n-3 PUFAs on people of different ages, and particularly those affected by AD and other degenerative diseases. A study conducted by Jiao et al. (2014) investigated the effects of n-3 PUFAs supplementation on cognitive function throughout the lifespan, from infancy to old age (Jiao, et al., 2014). (35) The randomized controlled trials involved in the study included 12,999 participants (1031 infants, 1517 children, 3657 adults, and 6794 elderly persons). The results of the study showed a significant improvement in cognitive development in infants, following n-3 PUFA treatment. However, n-3 PUFAs supplementation failed to promote cognitive function in 3 domains (composite memory, executive function, and processing speed) in children, adults, and the elderly. Only the attention domain was improved in the 3 age groups. Mostly importantly, n-3 PUFA supplements were not associated with in any improvement in cognitive decline or other effects of AD observed in the elderly (Jiao, et al., 2014). (36) A review conducted by Hooijimans et al. (2012) investigated the effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer's pathology in animal model of the disease. (37) The findings of the study showed that long-term use of omega -3 fatty acid supplementation decreased the omega-6/omega-3 FA ratio and resulted in a reduction of the amount of amyloid-[beta] in experimental animal models of AD (Hooijmans, Jong, Vries, & Ritskes-Hoitinga, 2012). (38) Besides increasing cognitive function, omega 3 supplementation also diminished the amount of neurons lost, especially in female animals. The findings recommended numerous clinical trials with objective of establishing the benefits of omega -3 fatty acids supplementation.

Glutathione

Extensive research shows that the lack of balance that exists between oxidant and antioxidant species is linked to the onset of a number of chronic conditions such as Alzheimer's disease and Parkinson's disease. Several studies indicate that oxidative stress plays a role in the aging process or pathogenesis of various conditions including neurodegenerative conditions. Indeed age has been identified as the most important risk factor for several neurodegenerative diseases, including AD. Studies have proposed that the process of aging is usually accompanied by the generation of reactive oxygen species and disruption of glutathione homeostasis in the brain. A study seeking to establish the role age in the changes that occur on glutathione and glutathionerelated enzymes was carried out by Zhu, Carvey, and Ling (2006) in young and aged rat siblings of both genders. (39) The findings of the study showed that a significant association between age and reduction of GSH in the mice brain areas that were examined. The reduction was associated with increased oxidation of GSH to glutathione disulfide (GSSG) and a decrease in the GSH.GSSG ratio. A diminished gamma-glutamylcysteine synthetase activity The findings of the study showed that aged animals were more likely to experience oxidative stress, insinuating their role in modelling age-related neurodegeneration in humans (Zhu, Carvey, & Ling, 2006). (40)

A review conducted by Mazzetti et al. (2015) reported on findings from specimens collected from patients and in vitro studies using cells or animal models, and it showed that there was an association between glutathione (GSH) depletion with AD and Parkinson's disease. (41) The review further established a significant decrease in the activity of glutathione transferase in some selected areas of the brain and in the ventricular cerebrospinal fluid (Mazzetti, Fiorile, Primavera, & Bello, 2015). (42) Another study conducted by Crack et al. (2006) reported consistent findings by establishing that the lack of glutathione peroxidase-1 exacerbated Abeta-mediated neurotoxicity in cortical neurons. (43) The used Glutathione peroxidase knockout mouse (Gpxl--/--) model to investigate how antioxidant played in neuropathologies. The findings of the study showed that antioxidant disparity results increasing susceptibility of Gpxl--/-- cells to Abeta toxicity. The findings supported the idea that oxidative stress contributes to the loss of neurons in AD (Crack, Clindins, Ali, Hertzog, & Iannello, 2006). (44)

Another review conducted by Braidy et al. (2015) investigated the potential options for replenishing the levels of GSH, the main endogenous antioxidant, as a therapeutic target for treating AD and other degenerative diseases. The review took note of the fact that administering GSH itself has a limited effect because of the unfavorable concentration gradient that exists between cytosol and plasma. This finding is further shown by the limited efficacy of cysteine prodrugs in elevating levels of depleted GSH in several in vitro and in vivo models. (45) These findings suggest that the decline of GSH in AD may be due to the down regulation of GSH homeostasis rather than a limitation in substrate. Homeostasis of cellular GSH levels is regulated by non-allosteric feedback inhibition exerted by GSH on glutamate cysteine ligase (GCL, which synthesizes GSH precursor y-glutamylcysteine (GGC) (Braidy, Zarika, Welch, & Bridge, 2015). (46) Therefore, in conditions where GSH homeostasis is down regulated, GGC plays the role of a crucialrate-limiting substrate for GSH synthetase (the enzyme responsible for condensing glycine with GGC to form the final thiol tripeptide). GGC may therefore hold a therapeutic potential for elevating the cellular levels of GSH (Braidy, Zarika, Welch, & Bridge, 2015). (47)

A study conducted by Tanel et al. (2007) focused on inhibition of acrolein, a highly electrophilic alpha, beta-unsaturated aldehyde which has been implicated in neurodegenerative diseases such as AD. (48) According to the study, the glutathione precursor, antioxidant N-acetylcysteine (NAC) can protect cells against acrolein-mediated apoptosis. During the study, ovary cells of Chinese hamster were exposed to a non-cytotoxic dose acrolein leading depletion of intracellular glutathione to 45% of the initial level. NAC, which increased the intracellular levels of glutathione by 30%, protected cells from cytotoxicity (loss of cell proliferation) and apoptosis induced by acrolein. This is achieved through a mechanism in which NAC diminishes acrolein-induced activation of the mitochondrial death pathway. Western blot analysis showed the ability of NAC to inhibit acrolein-induced bad translocation from the cytosol to the mitochondria, and the inhibition of Bcl-2 translocation from mitochondria to the cytosol (Tanel & Averill-Bates, 2007). (49) The findings also showed that NAC had no effect on the acrolein-induced Bax translocation to mitochondria and the liberation of cytochrome into the cytosol. Other noted effects of NAC were the inhibition of depolarization of membrane potential of the mitochondria, and the inhibition of acrolein-induced inhibition of procaspase-9 processing, enzymatic activity of caspase-9, -7, and -8, and polymerase cleavage. The findings of the study suggested that NAC could offer a potential remedy as a protective agent for people who risk exposure to acrolein (Tanel & Averill-Bates, 2007). (50)

Due to findings that show oxidative stress plays a central role in the development of AD, numerous therapeutic approaches, including the use of exogenous antioxidants have been proposed. Some studies have suggested the mobilization of the body's antioxidant system against the oxidative stress inherent in the brain of AD patients. This particularly should focus on the various strategies available for boosting the levels of glutathione in the brain (Butterfield, Pocernich, & Drake, 2002). (51)

Acetyl-L-Carnitine (ALC)

Acetyl-L-1 carnitine also referred to as ALCAR or simply ALC, an acetylated form of L-carnitine, is a compound that functions as an intracellular carrier of acetyl groups across the inner mitochondrial membrane. The compound has also been shown to possess neuroprotective properties, including the reduction of attention deficits in patient's suffering from AD. The compound is naturally produced by the human body but is often consumed as a dietary supplement for certain health benefits. ALCAR is synthesized in the body to provide a more bioavailable form of L-carnitine, a derivative of amino acid lysine (Calvani, Carta, Benedetti, Iannuccelli, & Caruso, 2006). (52) A study conducted by Wang et al. (2014) established that intraperitoneal administration of supplementary ALC caused partial reversal of scopolamine-induced memory and learning deficits in AD. (53) ALC was also able to reverse the impairment of long-term dendritic abnormalities, potentiation, and the impaired recruitment of synaptic protein (Wang, et al., 2014). (54) The findings of the study provided data on the potential use of ALC in the treatment of synaptic disorders experienced in AD and other neurodegenerative conditions.

A study conducted by Bianchetti, Rozzini, and Trabucchi (2003) investigated the effects of ALC in AD patients unresponsive to acetylcholinesterase inhibitors. (55) The open study evaluated the effect of ACL (2g/day orally for 3 months) in association with rivastigmine or donepezil in 23 mild cases of AD that had failed to respond to acetylcholinesterase inhibitor (ACheE-1) treatment (Bianchetti, Rozzini, & Trabucchi, 2003). (56) The clinical effects of the evaluation were by conducting an assessment of the cognitive functions, behavioral symptoms, and functional statuses following the intervention. The response rate increased from 38% to 50% after addition of ALC to the AChE-I, confirming that an approach that combines these drugs may offer better therapeutic benefits to AD patients (Bianchetti, Rozzini, & Trabucchi, 2003). (57) The efficacy of ALC for long-term treatment of AD was investigated by Spagnoli et al. (1991) in 130 patients who had been clinically diagnosed with AD. (58) The researchers employed 14 outcome measures to assess the cognitive and functional impairment. One year after treatment, both the treated and placebo groups worsened, with the treated group worsening and slower rate compared to the placebo group in 13 of the 14 outcome measures used. Analysis of patients with good treatment adherence showed a greater benefit compared to others (Spagnoli, et al., 1991). (59)

Many more studies have investigated the effects of ALC in Alzheimer's disease. A study conducted by John et al. (1998) assessed the longitudinal effects of ALCAR on patients diagnosed with AD. (60) The longitudinal, parallel-group, double-blind, placebo-controlled study was conducted in 24 outpatients sites across the US. A total of 334 patients diagnosed with probable AD were included in the study. Though the average rate of change was identical in the drug and placebo group on the ADAS scale, a multi-regression analysis showed a statistically significant age and drug interaction which revealed that the younger subjects were benefiting more from ALC treatment compared to older subjects (John, Brooks, Jerome, Carta, & Bravi, 2005). (61) The findings of the study showed that ALC slows down the progression of AD in younger patients, at a cut point of about 61 years, and the trilinear approach provided a better estimate of the average rate of change.

A study conducted by Gavrillova et al. (2011) investigated the role of ALC in the treatment of early stages of AD and vascular dementia. (62) The efficacy, tolerability, and safety of ALCAR were investigated during a 12-week, double-blind, placebo-controlled trial in patients with mild dementia caused by AD, and vascular dementia. ALCAR was administered in doses ranging from 2250 to 3000 a day. Effects on patients was assessed using MMSE, CGI scales and a number of neuropsychological tests (Gavrilova, Kalyn, Kolykhalov, Roschina, & Selezneva, 2011). (63) The results showed that the treatment effect of ALC was 2.8 times higher compared to placebo. Furthermore, CGI scores showed that the clinical improvement in AD were significantly higher compared to VD and was not related to severity or baseline of cognitive deficit (Gavrilova, Kalyn, Kolykhalov, Roschina, & Selezneva, 2011). (64) The findings of the study sug-gested that ALCAR could useful in the treatment of early stages of AD and VD.

In 1995, Pettegrew et al. conducted a small study to investigate the clinical and neurochemical effects of acetyl-L-carnitine in AD. (65) During the double-blind, placebo-controlled study, ALCAR was administered to 7 probable Alzheimer's disease patients who were compared using P magnetic resonance spectroscopic measures and clinical investigations to 5 placebo-treated probable AD patients and 21- ag matched health controls for a 1 year period (Pettegrew, Klunk, Panchalingam, Kanfer, & McClure, 1995). (66) Compared to placebo-treated patients, the ALCAR-treated patients showed a significantly less deterioration in their Mini-Mental status and Alzheimer's disease assessment Scale test scores. Additionally, the decreased levels of phosphomonoester levels observed in both acetyl-L-carnitine and Placebo normalized in the ALCAR group but not the placebo group (Pettegrew, Klunk, Panchalingam, Kanfer, & McClure, 1995). (67) This was the first study to investigate the effect of ALCAR on both clinical and neurochemical parameters.

A study conducted by Zhou et al. (2011) reported on the ability of acetyl-L-carnitine to attenuate homocysteine-induced Alzheimer-like histopathological and be-havioral abnormalities. (68) The study was based on the background that hyperhomocysteinemia could induce tau protein hyperphosphorylation, [beta]-amyloid (A[beta]) accumulation, and memory deficit as observed in AD. With an aim of identifying a possible treatment for AD, the researchers produced a hyperhomocysteinemia model by vena caudalis injection of homocysteine (Hcy) for 2 weeks and studied ALCAR effects in rats (Zhou, et al., 2011). (69) The researchers established that a simultaneous supplement of ALCAR could cause an improvement in the Hcy-induced memory deficits remarkably, with attenuation of tau hyper-phosphorylation and A[beta] accumulation. ALCAR supplementation almost eliminated the Hcy-induced tau hyperphosphorylation at multiple AD-sites (Zhou, et al., 2011). (70) It also suppressed the phosphorylation of [beta]- amyloid precursor proteins (APP). The researchers concluded that ALCAR could be a promising candidate for arresting Hcy-induced AD-like behavioral and pathological impairments.

Alpha-lipoic Acid

Alpha-lipoic acid (ALA) is a disulfide molecule that occurs naturally and with has been shown to possess anti-inflammatory and antioxidant properties. ALA plays several distinct roles in the pathogenic pathways of dementia, where it functions as a neuroprotective agent. Among other functions, ALA increases the production of acetylcholine, inhibits the production of hydroxy1 radical, and increases the process of reactive oxygen species elimination (Fava, et al., 2013). (71) Small epidemiological studies conducted over the past decade have provided evidence on the role played by ALA in patients suffering from AD. The studies report slowing down of cognitive impairment in patients suffering from AD or stabilization of cognitive functions during ALA intervention (Fava, et al., 2013). (72) In one of the studies conducted by Hager et al. (2007) 600mg of alpha-lipoic acid was given daily to nine patients with AD (receiving a standard treatment with choline-esterase inhibitors) over an observation period that lasted 12 months. (73) Two neuropsychological tests (the mini mental state exam, MMSE and the Alzheimer's disease assessment score subscale, ADAScog) showed that ALA treatment led to the stabilization of cognitive functions in the study groups (Hager, Kenklies, McFoose, Engel, & Munch, 2007). (74) Though the study was not randomized, placebo-controlled, and double-blinded, the findings showed the successful neuroprotective benefits that might be achieved by treating AD patients with alpha-lipoic acid.

B vitamins and folate

It is a well-known fact that high levels of homocysteine, an amino acid, is associated with brain shrinkage. On the other hand, B vitamins are also known to suppress homocysteine. A study conducted by Douaud et al. (2013) (75) investigated whether B-vitamin treatment could prevent gray matter atrophy associated with AD. The study which included a study group and a placebo group, both with high levels of homocysteine, established that B vitamins were able to lower the levels of homocysteine and thereby decrease brain atrophy and related decline in cognitive function (Douaud, et al., 2013). (76) Investigations into the association between folate, B vitamins, and serum levels of homocysteine in AD go back more than a decade. In 1998, a study conducted by Clarke et al. established that low levels of folate and vitamin B12 and elevated levels of homocysteine in blood were associated with AD (Clarke, et al., 1998). (77) Since then, several studies have supported the hypothesis that a high dose of B vitamin and folate could be beneficial in the prevention of cognitive decline in AD.

A study conducted by Aisen et al. (2008) sought to further this understanding by investigating the effect of high dose of B vitamin supplementation on cognitive decline in AD. (78) The multicenter, double-blind, randomized controlled trial of high dose folate, vitamin B6, and vitamin B12 supplementation in 409 patients suffering mild or moderate AD showed that a high dose of vitamin B supplements do not slow the cognitive decline in individuals with moderate to mild AD (Aisen, et al., 2008). (79)

Testosterone

Studies have established that low levels of testosterone in older men may be associated with the development of AD, and may also increase the risk of developing dementia. Several trials have reported that low levels of testosterone may be an independent predictor of rapid cognitive decline in older men who are diagnosed with early memory loss (Cherrier, et al., 2005). (80) It is on this basis that testosterone supplementation may be beneficial in AD. A study conducted by Cherrier et al. (2005) established that testosterone supplementation may be beneficial to certain cognitive functions in men with AD. (81)

Dimethylaminoethanol (DMAE)

DMAE (Dimethylaminoethanol) is an indirect pre-cursor of acetylcholine and is found in abundance in sardines and anchovies. Limited amounts of DMAE are also produced in the human brain. This natural compound has been used for some time for its ability to boost brain power. While there is limited evidence for its effectiveness in in Alzheimer's disease, DMAE is thought to be an effective supplement for treating memory lapses. It has also been shown to be effective in the treatment of disruptive and impulsive behaviors caused by ADHD. DMAE has also been incorporated in a nutraceutical formulation which also includes phosphoesters and antioxidants. The supplement is designed to improve neuronal functions, improving cognitive and memory abilities, and reversing the free radical damage caused by aging and neurodegenerative diseases. Studies have shown that DMAE might have memory boosting effects, which can be crucial in the treatment of usual memory lapses that occur with aging. Though evidence from thorough studies, a number of trials report memory improvement, particularly the short-term memory, as well as improved mental clarity, focus, and concentration. A small double-blind, placebo-controlled trial conducted by Fisman, Mersky, and Helmes (1981) investigated the effects of 2-dimethylaminoethanol in AD. (82) During the trial, 2-DMAE was prescribed to 27 patients with moderate to severe AD. Six of the 13 patients in the drug group were withdrawn within the first 5 weeks due to side effects that included drowsiness and retardation, and an increase in confusion and mild elevation of blood pressure (Fisman, Mersky, & Helmes, 1981). (83) The study did not find any significant benefit from the drug treatment.

Other studies have however reported positive findings when DMAE is combined or reacted with other compounds. A study conducted by Blin et al. (2009) investigated the effects of dimethylaminoethanol pyroglutamate (DMAE p-Glu) against memory deficits induced by scopolamine. (84) The study aimed at establishing the potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit. Both clinical and preclinical evaluations were used in the study. Results from rat experiments showed the ability of DMAE p-Glu to increase the extracellular levels of acetylcholine and choline in the medial prefrontal cortex, as evaluated by intracerebral microdialysis (Blin, et al., 2009). (85) This led to improvement in performance in a spatial memory test, and reduction in scopolamine-induced memory deficit in passive avoidance behavior. Results from clinical studies showed that DMAE p-Glu produced significant positive effects in scopolamine induced memory deficits. The findings of the study suggested that DMAE p-Glu might be useful in the reduction of memory deficits in patients suffering from cognitive impairment.

Phosphatidylserine

Phosphatidyl serine (PS) is an important phospholipid component of the cell membrane. In 2003, the Food and Drug Administration approved phosphatidylserine which allowed labels to state that the compound may reduce the risk of dementia and cognitive dysfunction in the elderly. This was however with a condition that a disclaimer be included on the grounds of the limited evidence on the ability of PS to reduce cognitive dysfunction in the elderly. A number of studies have been completed since then and there is increasing evidence that PS may offer some benefits in Alzheimer's disease. Studies conducted earlier has found PS to be a promising agent for the use in the treatment of AD. A study conducted by Crook et al. (1992) investigated the effects of phosphatidylserine in Alzheimer's disease. (86) The researchers investigated 51 patients who met the clinical criteria for probable AD, subjecting them to 12 weeks of treatment with a formulation of bovine cortex phosphatidylserine (BC-PS; 100mg t.i.d) or placebo. Patients treated with the drug improved o several cognitive measures relative to those who received placebo. The differences between treatment groups were more marked in patients with less severe cognitive impairment (Crook, Petrie, Wells, & Massari, 1992). (87) The findings of the study suggested that PS may be a promising candidate for study in the early stages of Alzheimer's. Another inquiry, a double-blind cross-over study was conducted by Engel et al (1992) to investigate the comparative effects of PS and placebo in patients with early dementia of Alzheimer's type. (88) During the study, 33 patients with mild primary degenerative dementia according to the DSM-II participated in the study and were subjected to Fidia, 300mg/dl of PS versus placebo. Both treatment phases lasted for 8 weeks with an 8-week washout phase in between a four-week washout phase before treatment phase one (Engel, et al., 1992). (89) Clinical global improvement ratings indicated significant improvement with BC-PS as opposed to placebo in during phase one treatment. The improvements were still noticeable in the subsequent wash-out and treatment phases. There were nonetheless no significant improvements as observed by the dementia rating scale, P300-latency or psychometric tests. A 16-channel EEG mapping findings snowed indicated higher power values in all frequency bands (except alpha), when compared to a healthy, younger group. BC-PS caused more reduction in the higher power values compared to placebo, shifting EEG power towards the normal values (Engel, et al., [992). (90) The findings of this study also showed positive benefits of PS in Alzheimer's disease.

In 2014, More, Freitas, and Rutenberg reported on previously unpublished early pilots that investigated the effects of soy lecithine-derived phoshatidylserine plus phosphatidic acid (PA) on memory, cognition, daily functioning, and mood in elderly patients with AD and dementia. (91) During the study, serum analysis was performed in healthy volunteers after a single PS+ PA ingestion. This was followed by a 3-month double-blind, placebo-controlled study to assess the influence of 3 PS+PA capsules a day or placebo on the memory and mood in non-depressive elderly people with memory problems (More, Freitas, & Rutenberg, 2014). (92) The List of Depressive Symptoms and the Wechsler Memory Scale were used in the analysis. Additionally, a 2-month, placebo-controlled, double-blind assessed the effect of 3 PS+PA capsules (300 mg PS + 240 mg PA/day) or placebo on mental health, emotional state, daily functioning, and self-reported general condition in patients with AD (More, Freitas, & Rutenberg, 2014). (93) The findings of the study showed that PS+PA had a positive influence on mood, cognition, and memory among elderly subjects. A short term supplementation of PS+PA in patients suffering from AD demonstrated a stabilizing effect on daily functioning, self-reported general condition, and emotional state. The researchers suggested a long-term study on PS+PA in Alzheimer's patients and other elderly with cognition and memory problems.

Herbal Extracts/Medicinal Plants

A number of herbal extracts such as Ginkgo Biloba, Bacopa monnieri, curcumin have been shown to possess protective properties against Alzheimer's Disease.

Ginkgo Biloba

The leaves of Ginkgo biloba have been used for thousands of years as a common treatment by the Chinese. Some studies have shown that Ginkgo biloba supplementation could be beneficial in AD. The studies show that the administration of a high dose of Ginkgo could be beneficial for cognition and accompanying psychopathological symptoms (Janssen, et al., 2010). (94) The effects of Ginkgo biloba and its extracts in AD have been corroborated by findings of animal model studies. A study conducted by Liu et al. (2015) on the Long-term treatment with Ginkgo biloba etract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer's disease. (95) The researchers investigated the anti-inflammatory effects and the underlying molecular mechanisms of Ginkgo biloba extract EGb 761 when administered to TgCRND8 AD mice, which is known to overexpress human Alzheimer's amyloid protein (APP) particularly in neurons (Lui, et al., 2015). (96) Following the two to five-month treatment with EGb 761 as a dietary supplement, cognitive function was increased in the mice as measured by the Barnes Mazes test. The supplement also lessened the loss of synaptic structure proteins, including Munc 18-1, PSD-95, and SNAP 25. Other benefits included the inhibition of microglial inflammatory activation, activation of autophagy in the microglia, reduction of A[beta]-induced microglial secretion of TNF- [alpha] and IL- [beta] and the activation of caspase-l(Lui, et al., 2015). (97) The researchers concluded that long-term treatment with Ginkgo biloba extract EGb 761 ameliorates Alzheimer's pathology through A[beta]-directed and anti-inflammatory mechanisms. Other studies have shown that if Ginkgo biloba is combined with other supplements, then the risk of AD may be reduced further. A study conducted by Bun et al. (2015) investigated how a combination of supplements may reduce the risk of AD among elderly Japanese with normal cognition. (98) The researchers used multiple supplements in order to counter the complex and multifactorial nature of AD. During the study, community dwelling volunteers were provided with daily capsules that contained n-3 polyunsaturated fatty acid, Ginkgo biloba leaf dry extracts, and lycopene for 3 years. The findings of the study showed that higher adherence to supplementation was associated with lower incidence of AD and this was established during follow up period (Buns, et al., 2015). (99)

Curcumin

Tumeric, (Curcuma longa, or Curcumin) has been known to possess anti-inflammatory properties for several centuries. Extensive research carried out in the past three decades has shown that the anti-inflammatory properties exhibited by turmeric are usually due to a diferuloylmethane identified as curcumin. Several studies have been carried out in a bid to identify the effect of curcumin on numerous conditions such as pulmonary, neurodegenerative, metabolic, neoplastic, autoimmune, and cardiovascular diseases. Quite a number of studies have been carried out on the effectiveness of curcumin in the treatment of Alzheimer's disease. While basing on the evidence that shows a pathological change of amyloid [beta] (A[beta]) to be the initiating event in AD and the evidence that supports the effectiveness of curcumin in treating AD pathology, a study conducted by Yanagisawa et al. (2015) investigated the effects of curcumin and two novel derivatives, FMeC 1 and FMeC2 on AD pathology in APPswe/PS 1 dE9 double transgenic mice. (100) The results of the study showed that mice fed on a chow diet containing FMeCl for 6 months showed a reduction in insoluble A[beta] deposits and glial cell activity in addition to reduced cognitive deficits, compared to mice that were subjected to a control diet with either curcumin or FMEeC2 (Yanagisawa, et al., 2015). (101) Both FMeCl and curcumin were able to modulate the formation of A[beta] aggregates, however, only FMeCl showed ability to attenuate cell toxicity due to A[beta] (Yanagisawa, et al., 2015). (102)

A study conducted by Zhai et al. (2015) (103) investigated the potential of a series of new asymmetric curcumin analogues as multifunctional agents in the treatment of AD. The results of the study showed that the compounds had a better inhibitory properties against AD aggregation as compared to curcumin (Zhai, et al., 2015). (104) A study of oxygen radical absorbance capacity (ORAC) also showed that the compounds had better antoxidative properties compared with Trotox (reference compound). The findings of the study showed that synthetic asymmetric curcumin derivatives could offer potential multifunctional agents for the treatment of AD (Zhai, et al., 2015). (105)

Bacopa Monnieri

Bacopa monnieri is an herb found in wetlands around the globe. Bacopa is a key medicinal herb that has traditionally been used by the Indians as a neurological tonic and an enhancer of cognitive functions. Studies on the plant are still ongoing, with preliminary findings indicating that it could in possession of important neuroprotective properties. A study conducted by Singh, Murthy, and Ramassamy (2010) investigated the modulation of hydrogen peroxide and acrolein-induced oxidative stress, mitochondrial dysfunctions and redox regulated pathways by Bacopa monniera extract. (106) The study was based on the background that acrolein is a key by-product of lipid peroxidation, and an important marker of oxidative stress through adduction of cellular nucleophilic groups. Levels of acrolein are found elevated in brains of AD patients, particularly in the vulnerable regions of the brain. With knowledge of the long history of use of Bacopa as a memory-enhancing therapy among Indians, the researchers sought to establish the neuroprotective effects of the standardized extracts of Bacopa against acrolein and H2O2. The results of the study showed that a pre-treatment with Bacopa extract protected the human neuroblastoma cell line SK-N-SH against acrolein and H2O2 (Singh, Muthy, & Ramassamy, 2010). (107) The study demonstrated that Bacopa pre-treatment had a significant inhibiting effect on the generation of intracellular reactive oxygen species in addition to preserving the mitochondrial membrane potential. Bacopa pretreatment also prevented the modifying effect on several redox regulated proteins that favor cell survival against oxidative stress. The findings of the study provided strong evidence that Bacopa monnieri may protect human neuroblastoma cells against acrolein and H2O2 by inhibiting different mechanisms involved in AD pathophysiology, and could have a therapeutic application in protection against AD (Singh, Muthy, & Ramassamy, 2010). (108) A few more animal studies have verified the positive benefits that may be obtained from Bacopa monnieri supplementation in AD. A study conducted by Saraf et al. (2011) reported on the ability of Bacopa monniera to attenuate scopolamineinduced impairment of spatial memory in mice. (109) Scopolamine is an anticholinergic agent which has in the put forth as an attractive amnesic agent for discerning the action of antimnesic drugs that are under investigation. The researchers sought to investigate whether Bacopa monnieri could ameliorate scopolamine-induced spatial memory impairment using water maze mouse model. The objective of the study was to understand the effect of B. monnieri on amnesia induced by scopolamine. The findings of the study showed that B. monnieri had the ability to reverse both anterograde and retrograde amnesia induced through scopolamine impairment of the acquisition and retrieval memory in mice (Saraf, Prabhakar, Khanduja, & Anand, 2011). (110) The findings of the study suggested that Bacopa's effect on cholinergic system could be useful in the development of alternative therapeutic approaches for the treatment of AD. The findings were corroborated by another study conducted by Uabundit et al. (2010) which investigated the neuroprotective effects of Bacopa monnieri in Alzheimer's disease model. (111) The study specifically sought to establish the effect of alcoholic extract of Bacopa on neurodegeneration and cognitive function in animal model of ethycholine aziridinium ioninduced AD. During the study, the researchers provided Male Wister rats with oral administration of alcoholic Bacopa monnieri extracts, at a dose of 40 to 80 mg/kg BW (Uabundit, Wattanathorn, Mucimapura, & Ingkaninan, 2010). (112) The extract was administered via a feeding needle for 2 weeks before and a week after bilateral AF64A intracerebroventricular admin-istration. The Morris water maze test was then used to test the rats for spatial memory and histological techniques used to determine the density of cholinergic neurons. The results of the study showed that Bacopa monnieri extract improved the escape latency time (p<.01) in the Morris water maze test (Uabundit, Wattanathorn, Mucimapura, & Ingkaninan, 2010). (113) The extract also mitigated neuron reduction and cholinergic neuron densities. The findings of the study furthered the evidence on Bacopa monnieri's potential as a cognitive enhance and a neuroprotective agent against AD.

Saffron (Crocus Savitus)

Saffron is a Middle-Eastern herb that is known to possess strong antioxidant properties. Its major constituents include crocin, crocetin, safranal can also be classified as antioxidants and share structural similarities with other antioxidants, such as zeaxanthin. The role of oxidative stress in many degenerative diseases, including DA, there has been an increasing interest in saffron supplementation (Broadhead, Chang, Grigg, & McCluskey, 2015). (114) In vitro studies in animal models have shown that saffron and its major constituents may be of great therapeutic benefit to a wide range of diseases, such as AD, cardiac ischemia, and age-related macular degeneration. There is however incomplete data on the particular benefits that could be accrued from saffron supplementation in Alzheimer's.

Omani figs fruits

The modifying effect of Omani fruits on oxidative stress is thought to have some benefits in AD. A study conducted by Subash et al. (2014) on chronic dietary supplementation of 4% figs on the modification of oxidative stress in AD transgenic (Tg) mouse model. (115) During the study, the researchers assessed the changes in oxidative stress/antioxidants, plasma A[beta] and membrane bound enzymes present in the cerebral cortex and hippocampus of AD mice Tg2576 after subjecting the mice to dietary supplementation of Omani figs fruits for 15 months, conducted together with spatial and learning test (Subash, Essa, Al-Asmi, Al-Adawi, & Viashnav, 2014). (116) The Alzheimer's Tg mice placed on a control diet showed a significantly impaired ability to learn compared to a wild type of mice on similar diet and the Tg mice fed on figs. Mice that were treated with 4% figs showed an increased ability to attenuate oxidative stress due to AD, as evidenced by the decreased level of lipid peroxidation, protein carbonyl, and the successful restoration of antioxidant status. Fig treatment led to restoration of altered of membrane bound enzymes such as Na(+) K(+) ATPase and acetylcholinesterase (AChE) in the brain regions of the AD Tg mice. The fig treatment was also able to reduce plasma levels of A[beta] (1-40, 1-42) suggesting a corresponding delay in the formation of plaques (Subash, Essa, Al-Asmi, Al-Adawi, & Viashnav, 2014). (117) The positive findings of the study might have been due to the high amount of natural antioxidants in the figs. Further investigation was suggested to establish how figs could be used to provide a novel therapeutic approach in AD.

Summary

Findings show that nutritional deficiency could be playing a role in the etiology of Alzheimer's disease. Based on this background, we sought to conduct reviews on dietary supplements, herbal extracts, and other supplements that can offer benefits by preventing or improving Alzheimer's disease. Reviewed studies show that dietary interventions such as Mediterranean diet and nutraceutical formulation can reduce the risk of AD. A number of specific nutritional compounds and herbal medications have also found to play some protective role. Those cited in this paper include Saffron, Omani fruits, Omega-3 fatty acids, curcumin, glutathione, Acetyl-L-carnitine, Alpha-lipoic acid, B vitamins, Ginkgo Biloba, flavonoids, polyphenols, DMAE among others. Some of these agents/extracts have not been fully investigated and more studies are still required to understand specific effects in AD.

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by: Steven Petrosino, Ph.D and Boaz Nyona Matende, BS
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