Index

Abstract

Introduction: Alzheimer's disease (AD) has no effective treatment, nor does its “precursor” mild cognitive impairment (MCI). Methods: This is a nine-month, randomized, open, pilot trial. We are using four dietary changes and twelve supplements to slow progression of dementia in patients with MCI. Patients were randomly assigned to the diet-plus-supplement intervention group (1) or to the supplement intervention group (2). Supplementary cobalamin, folate, and S-adenosylmethionine (SAM) may reduce secretase/amyloid production. Antioxidants coenzyme Q10, ascorbates, gamma-tocopherol, and extracts of ginkgo biloba and centella asiatica were used. Zinc, copper, manganese, and selenium support endogenous antioxidant enzymes. Dietary interventions include berries, walnuts, decreasing dietary advanced glycation endproduct intake, and limiting saturated fatty acids to seven percent of calories. Results: In this small pilot study, it was surprising that participants in the supplement-only group improved more than in the supplement-plus-diet group. The Mini Mental State Examination (MMSE) was administered at baseline and every 3 months. While 9.6% of MCI patients normally degenerate to dementia each year, over nine months, participants in the supplement-only group had an average improvement in the MMSE of 10 points (out of 30 points). At the end of the intervention, average score was 29 out of 30 points, indicating a normal cognitive state. In the food-plus-supplement group no degeneration was seen, although improvement was also not seen. Conclusions: This multifaceted nutritional intervention had a positive impact by slowing the progression of dementia and reducing the risk of Alzheimer’s disease. A larger, multicenter trial is needed to confirm these results.  

Keywords: Dementia, Mild cognitive, Impairment, Nutrition, Antioxidants, Amyloid plaque, Alzheimer’s disease, Supplements, Cognition, Memory.

Received: 12 October 2018 / Revised: 20 November 2018 / Accepted: 17 December 2018/ Published: 2 January 2019


1. INTRODUCTION

There has been an alarmingly sharp increase in deaths from Alzheimer’s disease (AD) between 1979 and today, with further increases forecast. According to the latest United States Centers for Disease Control figures, per 10,000 in the population, deaths from Alzheimer’s disease increased from 3 in 1979 to 268 in 2013 (reported in 2016) [1]. Although cholinesterase inhibiting drugs and N-methyl-D-aspartate receptor antagonist drugs may temporarily improve memory, they may not be able to stop beta-amyloid plaque buildup or slow nerve membrane disruption and brain neuron death [2].

This intervention trial tested the ability of a multi-faceted nutritional intervention to slow beta-amyloid plaque buildup and to slow nerve membrane disruption and brain neuron death. The hypothesis was that these interventions would slow the progression of mild cognitive impairment (MCI) into AD.

1.1. Slowing Amyloid Plaque Production: Folate, Cobalamin, Homocysteine, and SAM

Beta-secretase and gamma-secretase are two enzymes expressed in brain neurons that can abnormally cleave amyloid precursor protein (APP) into amyloid peptides [3]. These amyloid peptides can be toxic and can contribute to the formation of amyloid plaques, a signature feature of Alzheimer’s disease. If we can reduce beta- and gamma-secretase biosynthesis, then there may be less abnormal cleavage of the APP [4]. Less abnormal cleavage of the APP can lead to less amyloid plaque buildup from amyloid peptides. There are no drugs available to slow the formation of the secretase enzymes. Pharmaceutical attempts to slow the production of gamma- and beta-secretase enzymes have not been successful. However, there is evidence that expression of these two enzymes can be decreased by supplying folate and cobalamin to assist the transformation of homocysteine into s-adenosylmethionine (SAM). SAM has the ability to quench, through methylation, the production of beta- and gamma-secretase.

When adequate folate and cobalamin are present, homocysteine can be converted to SAM [5]. SAM, through methylation of DNA, quenches the expression of the presenilin-1 gene, thus reducing beta-secretase biosynthesis [6]. Also, reduced homocysteine increases DNA methyltransferases, which reinforces DNA methylation, leading to decreased beta-secretase biosynthesis [7].

We would expect to find lower than normal levels of SAM in AD patients, and this has been found. The severely low levels of SAM that have been found in the cerebrospinal fluid and in all brain regions tested in AD patients may partially explain the abnormal cleavage of APP and high levels of amyloid-beta production in these patients [8].

When folate and cobalamin are not taken in adequate amounts, less homocysteine is converted to SAM. This can result in elevated homocysteine levels. Elevated homocysteine in plasma has been found to be a risk factor for the onset of AD [9]. In fact, high levels of homocysteine were found to quadruple the risk of dementia and AD [10]. Patients with confirmed AD were four times as likely to have elevated homocysteine [11]. Interestingly, higher homocysteine levels in the brain are also associated with the accumulation of phosphorylated tau, one of the signature features of AD [12].

Low levels of folate might reduce the biosynthesis of SAM from homocysteine, leading to increased rates of AD. Low levels of folate were found to triple the risk of vascular dementia and AD [10]. Patients with AD were three times as likely to have low folate levels [11]. In order to ensure adequate conversion of homocysteine to SAM, we supplied participants with an oral dosage of folic acid of 600 micrograms (mcg) daily. The daily tolerable upper intake level for folic acid is 1000 mcg.

Patients with confirmed AD were four times as likely to have low cobalamin compared to people without AD [11]. Low levels of cobalamin might limit production of SAM, leading to more production of beta- and gamma-secretase enzymes. In order to limit production of amyloid plaques, we supplied a daily dosage of 240 mcg of methylcobalamin for participants. Since absorption is often one percent of the dose, Quadros [13] 240 mcg can supply the required 2.4 mcg recommended daily allowance for cobalamin. There is no upper limit set for this non-toxic B-vitamin.

In addition to supplying folic acid and cobalamin to boost SAM production, we supplied exogenous SAM in an oral dosage of 200 milligrams (mg) daily, given in the morning. This supplemental SAM may be able to further limit the production of amyloid plaques by limiting the abnormal cleavage of the APP.

1.2. Advanced Glycation Endproducts

In advanced AD, up to half of the original brain neurons may be lost. The damage and death of these neurons may be related to excess oxidation with inadequate antioxidants—both exogenous and endogenous. The high percentage of very long-chain and highly unsaturated fatty acids in brain cell membranes increases their vulnerability to oxidation. Advanced glycation endproducts (AGEs) may increase oxidation and death of brain neurons. In addition, AGEs may increase inflammation in the brain.

AGEs can be formed when proteins and sugars react. AGEs can be formed during cooking or storage of food and can be absorbed from the diet. AGEs can also be created in the bloodstream during hyperglycemia. AGEs are deformed proteins that have been polymerized and cross-linked. AGEs are proteins that are difficult for our bodies to break up and eliminate. AGE formation may represent an early, if not initial, event in the progression of AD by increasing oxidation, inflammation, and neuronal death in the brain [14]. Serum concentration of AGEs is associated with increased cognitive decline in elderly individuals [15].

AGEs were three times as high in the brains of AD patients compared to non-AD brains [16]. AGEs were found in both amyloid plaques and tau tangles [16]. AGEs can generate an estimated 50 times as many free radicals when compared to normal proteins [17]. When AGEs accumulate in amyloid plaques in the brain, they can cause increased lipid peroxidation of both cellular membranes and mitochondrial membranes [18]. Cell death from oxidation of cellular membranes may be one of the mechanisms of pathology in AD.

AGEs, although proteins or peptides, can be taken into the bloodstream from food. However, only the shorter AGE peptides are absorbed, and studies show that they are indeed absorbed into the blood [19]. Ten to thirty percent of the ingested AGEs may be absorbed. AGE levels in the blood have been shown to double after a meal high in foods containing AGEs. When AGEs cross the blood-brain barrier with the RAGE receptor (receptor for advanced glycation endproducts), they may trigger inflammation in the brain [20].

To reduce AGE intake, guidelines for this intervention trial discouraged cooked by broiling, barbequing, or frying of meat, poultry, or fish. Aged cheeses are also eliminated from intervention diets. Compliance has been an issue with these food preparation changes.

1.3. Antioxidants to Slow Progression of Dementia

Certain antioxidants have been found to exert protective effects on the easily-oxidized docosahexaenoic acid (DHA) and arachidonic acid in neuronal membrane phospholipids. Antioxidants are also crucial for protecting mitochondrial membranes. Neuronal death is a key factor in AD and antioxidants can reduce membrane damage leading to neuronal apoptosis [21].

1.4. Vitamin E

Vitamin E is a lipid-soluble vitamin with antioxidant properties that may decrease free radical mediated damage in neuronal cell membranes [22]. Many, but not all, observational studies have suggested a protective effect of vitamin E for the prevention of cognitive decline and AD [23]. One study looking at levels of vitamin E in blood found that the participants in the lowest tertile of vitamin E blood levels had more than twice the chance of cognitive impairment and dementia (OR of 2.2 and 2.6, respectively) compared to higher levels [24]. An Italian study found that those in the lowest tertile of plasma delta-tocopherol had an odds ratio of 3.87 for dementia compared to the highest tertile [25]. Another study showed that vitamin E in food lowered the risk of developing AD by two thirds (67%) [26]. A recent study found that those with either MCI or AD had 85% lower odds of being in the highest tertile of plasma total vitamin E [27].

Vitamin E supplements used in studies are often synthetic all-racemic alpha-tocopherol, a mixture of eight isomers, only one of which is alpha-tocopherol [28]. Four of these synthetic isomers are inactive and three are less active than rrr-alpha-tocopherol. Vitamin E supplements used in studies may also not include gamma- and delta-tocopherol. Mixtures of the various tocopherol forms, rather than alpha-tocopherol alone, may be important in the vitamin E protective association with Alzheimer disease [29]. Vitamin E that included all tocopherols was effective in cutting dementia risk in half (HR 0.46) [21]. Another study found that gamma-tocopherol was found to be more effective in scavenging free radicals than alpha-tocopherol [30]. A recent study of postmortem brains showed an association of less amyloid-beta and lower neurofibrillary tangle severity in brains with higher gamma-tocopherol, but not alpha-tocopherol content [31]. 

Intervention patients were encouraged to eat one ounce each of English walnuts and sunflower seeds daily to supply gamma- and alpha-tocopherol (respectively). A blend of tocopherols was part of the supplement program, providing 500 mg gamma-tocopherol, 150 mg delta-tocopherol, 60 mg rrr-alpha-tocopherol, and 11 mg beta-tocopherol daily. Vitamin C is an antioxidant and is necessary so that vitamin E can continue its antioxidant action [32]. Participants received 800 mg of ascorbated vitamin C daily split into two doses.

1.5. Berries and Anthocyanidins

Blueberries, strawberries, and red grapes contain antioxidant and anti-inflammatory flavonoids, other polyphenols, and also antioxidant carotenoids [33]. The polyphenol anthocyanins in these berries and grapes have been shown to be helpful in slowing the aging of the brain [34]. In the Nurses’ Health Study, anthocyanins were found to cross the blood-brain barrier and localize in the hippocampus. Those who ate more berries delayed dementia for an average of 2 years [35]. Concord grape juice contains polyphenol compounds which have antioxidant and anti-inflammatory properties [36]. Dieticians instructed intervention participants to include one cup of these antioxidant fruits daily. Alternatively, participants were allowed to drink a cup of Concord grape juice.

1.6. Endogenous Antioxidant Enzymes: Co-Factor Minerals

The endogenous antioxidant superoxide dismutase requires the necessary mineral co-factors copper, zinc, and manganese [37]. Another endogenous antioxidant, glutathione peroxidase, requires selenium to perform its antioxidant functions. Selenium was found to be significantly lower in AD patients [38]. These four minerals were included in the supplements for intervention participants.

1.7. Coenzyme Q10

Coenzyme Q10 (CoQ10) is the only endogenous fat-soluble antioxidant in humans. It is on the inner leaflet of the mitochondrial membrane where CoQ10 is most essential, scavenging free radicals produced by the aerobic production of energy [39]. CoQ10 is also necessary for aerobic energy production in its role in complex I of the electron transfer chain [40]. CoQ10 may be helpful in reducing the oxidative damage that precedes clinical and pathological AD symptoms. CoQ10 can reduce amyloid-beta deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline [41]. CoQ10 is potentially useful for attenuating amyloid pathology in Alzheimer's disease [42]. Intervention supplements included 200 mg CoQ10 daily.

1.8. Saturated Fatty Acids, Cholesterol, and AD

Atherogenic disease can start between the ages of two and eight [43]. Atherosclerosis is promoted principally by the intake of three saturated fatty acids (lauric, myristic, and palmitic acids) found in animal fats [44]. In AD there is often a component of vascular disease that can lead to concomitant vascular dementia [45]. Higher levels of saturated fat in the diet were found to greatly increase the risk of dementia [46]. Dietary animal fats were found to double the risk of AD [47].

In a large Danish study spanning many decades, it was found that people with elevated blood cholesterol at midlife were three times as likely to get AD as were those with lower cholesterol [48]. Conversely, high levels of high-density lipoproteins (HDL) cut the risk of AD in half [49].

When there are low levels of HDL and high levels of low-density lipoproteins (LDL), beta- and gamma-secretase enzymes are over-produced. Thus, more amyloid plaques may be created [50]. Higher cholesterol levels were also associated with increased production of the amyloid precursor protein, also potentially increasing amyloid-beta [51].

To reduce amyloid plaque production and to reduce vascular dementia in AD, participants were required to restrict their saturated fatty acids to seven percent of their caloric intake.

2. MEDICAL PLANTS TO TREAT AD

This intervention trial included two medical plants that have been shown to be helpful in AD.

2.1. Ginkgo Biloba

Ginkgo biloba has been found in a meta-study of double-blind, placebo-controlled trials to be helpful in delaying the onset of AD and in treating AD [52]. Evidence suggests that ginkgo biloba protects hippocampal neurons against cell death induced by beta-amyloid [53]. In a 24-week, randomized, placebo-controlled, double-blind study in patients with mild to moderate AD, ginkgo biloba improved memory as well as donepezil did [54]. The ginkgo biloba group showed a low dropout rate, which indicates that ginkgo biloba is well tolerated.

Improvement from ginkgo biloba may continue from 3 to 12 months. One study that looked at combined cholinesterase inhibitors and ginkgo biloba treatment showed MMSE scores improving 1 point in 6 months and 2 points in 12 months, while cholinesterase inhibitors alone showed a decreased score of about 1.4 points [54]. Ginkgo biloba is contraindicated for people on blood thinners, such as warfarin. Screening for this trial rejected patients on blood thinners. Daily dosage for ginkgo biloba extract was 160 mg.

2.2. Centella Asiatica

A recent study found that centella asiatica lowered beta-amyloid plaque in the hippocampus [55]. This study also showed that centella asiatica functions as an antioxidant to reduce free radical damage in membranes. Another study showed that centella asiatica boosted two enzymes that reduce free radical damage: glutathione peroxidase and catalase [56].A six-month study in healthy middle-aged patients showed that centella asiatica capsules improved the average score of the MMSE from 25 to 28, a 10% improvement [57]. A placebo-controlled, 60-day study showed that centella asiatica reduced the age-related decline in cognitive function in healthy middle-aged and elderly adults [58]. Centella asiatica side effects in this study seemed positive as it was noted to lower blood pressure and improve sleep. Our trial used 300 mg centella asiatica extract daily.

3. METHODOLOGY

Inclusion Criteria:

Exclusion Criteria:

Trial Site, Participants:

Prevention and Clinical Trial Unit, Hawaii Alzheimer’s Disease Center at Hawaii Pacific Neuroscience Center, Kailua and Honolulu, Hawaii. Two participants were in the supplement-only group and one in the supplement-plus-diet group.

Summary of Interventions:

Daily Supplements:

Dietary Protocol:

Reduce AGE intake: intake of broiled, barbequed, or fried meat, poultry, or fish was discouraged. Aged cheeses were also eliminated from intervention diets. One ounce of ground English walnuts and one ounce of ground sunflower seeds, taken daily when possible. Blueberries, strawberries, or red grapes, one cup or more, or one cup Concord grape juice taken daily. Saturated fatty acids were restricted to seven percent of caloric intake.

Registered dietitians taught dietary-intervention participants to implement the dietary changes from a standard script, and gave them a cookbook containing recipes to help them stay on the diet. The subjects in the 2 treatment groups received daily phone calls for the first 2 weeks to check on dietary supplement and dietary protocol compliance. After the initial 2 weeks, the subjects received phone calls every week.

4. RESULTS

Average MMSE scores in the supplement-only group at baseline were 19—just slightly lower than the lower limit for MCI, which is 20-25. This may have indicated a slight drop in cognition since diagnosis of MCI and prior to the study commencement. At the end of nine months the average score was 29, indicating a normal cognitive state. This was an increase in 10 points out of 30. The MMSE score did not change much in the supplement-plus-food group. This may indicate some protection from normal, predicted cognitive degeneration. The average progression of MCI to dementia is highly variable. In a meta-analysis of 41 studies, the average yearly clinical rate of progression from MCI to dementia was found to be 9.6% [59].

5. RESULTS & DISCUSSION

The trial was limited by the small number of participants. Enrollment was made more difficult because of the inclusion/exclusion requirements, coupled with finding participants willing to change their diet. Many elder participants were already taking multiple medications and objected to taking 7 more tablets or capsules daily.

The combination of nutritional strategies may have been responsible for the improvement in clinical memory and cognition scores.

6. CONCLUSION

This multifaceted nutritional intervention had a positive impact slowing the progression of dementia and reducing the risk of Alzheimer’s disease. Supplements designed to reduce oxidation and brain cell death may be effective in slowing the progression of AD. Supplements and dietary changes that limit the production of amyloid plaques may also slow progression of AD. A larger, multicenter trial is needed to confirm these results.

Funding: This study received no specific financial support.   
Competing Interests: The authors declare that they have no competing interests. 
Contributors/Acknowledgement: Ethics approval was by the Internal Review Board (IRB) of the office of research compliance, human studies program, University of Hawaii (CHS#21491). Supplements were donated by Life Extension Foundation, which had no role in designing or running the trial. We want to thank Hawaii Pacific Neuroscience for donating staff, clinic space, and doctors’ time to this trial. All authors read and approved the final manuscript.

REFERENCES

[1]          X. J., S. Murphy, K. Kochanek, and B. Bastian, "Deaths: Final data for 2013," National Vital Statistics Reports, vol. 64, pp. 1-119, 2016.

[2]          H. Tayeb, H. Yang, B. Price, and F. Tarazi, "Pharmacotherapies for Alzheimer's disease: Beyond cholinesterase inhibitors," Pharmacology & Therapeutics, vol. 134, pp. 8-25, 2012.Available at: https://doi.org/10.1016/j.pharmthera.2011.12.002.

[3]          C. Venugopal, C. Demos, R. K. Jagannatha, M. Pappolla, and K. Sambamurti, "Beta-secretase: Structure, function, and evolution," CNS Neurol Disord Drug Targets, vol. 7, pp. 278-294., 2008.Available at: https://doi.org/10.2174/187152708784936626.

[4]          F. Panza, V. Frisardi, C. Capurso, A. D'Introno, A. Colacicco, A. Di Palo, and V. Solfrizzi, "Polyunsaturated fatty acid and S-adenosylmethionine supplementation in predementia syndromes and Alzheimer's disease: A review," The Scientific World Journal, vol. 9, pp. 373-389, 2009.Available at: https://doi.org/10.1100/tsw.2009.48.

[5]          D. Smith, Y. Smulders, H. Blom, J. Popp, F. Jessen, A. Semmler, and M. Linnebank, "Determinants of the essential one-carbon metabolism metabolites, homocysteine, S-adenosylmethionine, S-adenosylhomocysteine and folate, in cerebrospinal fluid," Clinical Chemistry and Laboratory Medicine, vol. 50, pp. 1641-1647, 2012.Available at: https://doi.org/10.1515/cclm-2012-0056.

[6]          A. Oikonomidi, P. Lewczuk, J. Kornhuber, Y. Smulders, M. Linnebank, A. Semmler, and J. Popp, "Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta," Journal of Neurochem, vol. 139, pp. 324-332, 2016.Available at: https://doi.org/10.1111/jnc.13766.

[7]          A. Fuso, L. Seminara, R. Cavallaro, F. D'Anselmi, and S. Scarpa, "S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production," Molecular and Cellular Neuroscience, vol. 28, pp. 195-204, 2005.Available at: https://doi.org/10.1016/j.mcn.2004.09.007.

[8]          M. Linnebank, J. Popp, Y. Smulders, D. Smith, A. Semmler, M. Farkas, and H. Kölsch, "S-adenosylmethionine is decreased in the cerebrospinal fluid of patients with Alzheimer’s disease," Neurodegenerative Diseases, vol. 7, pp. 373-378, 2010.Available at: https://doi.org/10.1159/000309657.

[9]          S. Seshadri, A. Beiser, J. Selhub, P. F. Jacques, I. H. Rosenberg, R. B. D'agostino, P. W. Wilson, and P. A. Wolf, "Plasma homocysteine as a risk factor for dementia and Alzheimer's disease," New England Journal of Medicine, vol. 346, pp. 476-483, 2002.

[10]        P. Quadri, C. Fragiacomo, R. Pezzati, E. Zanda, G. Forloni, M. Tettamanti, and U. Lucca, "Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia," The American Journal of Clinical Nutrition, vol. 80, pp. 114-122, 2004.Available at: https://doi.org/10.1515/cclm.2004.208.

[11]        R. Clarke, A. D. Smith, K. A. Jobst, H. Refsum, L. Sutton, and P. M. Ueland, "Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease," Archives of Neurology, vol. 55, pp. 1449-1455, 1998.Available at: https://doi.org/10.1001/archneur.55.11.1449.

[12]        E. Sontag, V. Nunbhakdi-Craig, J.-M. Sontag, R. Diaz-Arrastia, E. Ogris, S. Dayal, S. R. Lentz, E. Arning, and T. Bottiglieri, "Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation," Journal of Neuroscience, vol. 27, pp. 2751-2759, 2007.Available at: https://doi.org/10.1523/jneurosci.3316-06.2007.

[13]        E. V. Quadros, "Advances in the understanding of cobalamin assimilation and metabolism," British Journal of Haematology, vol. 148, pp. 195-204, 2010.Available at: https://doi.org/10.1111/j.1365-2141.2009.07937.x.

[14]        R. J. Castellani, P. L. Harris, L. M. Sayre, J. Fujii, N. Taniguchi, M. P. Vitek, H. Founds, C. S. Atwood, G. Perry, and M. A. Smith, "Active glycation in neurofibrillary pathology of Alzheimer disease: Ne-(carboxymethyl) lysine and hexitol-lysine," Free Radical Biology and Medicine, vol. 31, pp. 175-180, 2001.Available at: https://doi.org/10.1016/s0891-5849(01)00570-6.

[15]        M. S. Beeri, E. Moshier, J. Schmeidler, J. Godbold, J. Uribarri, S. Reddy, M. Sano, H. T. Grossman, W. Cai, and H. Vlassara, "Serum concentration of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive decline in elderly individuals," Mechanisms of Ageing and Development, vol. 132, pp. 583-587, 2011.Available at: https://doi.org/10.1016/j.mad.2011.10.007.

[16]        H.-J. Lüth, V. Ogunlade, B. Kuhla, R. Kientsch-Engel, P. Stahl, J. Webster, T. Arendt, and G. Münch, "Age-and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer's disease brains," Cerebral Cortex, vol. 15, pp. 211-220, 2005.Available at: https://doi.org/10.1093/cercor/bhh123.

[17]        S. Bengmark, "Amplifiers of systemic inflammation-The role advanced glycation and lipoxidation end products in foods," Kuwait Medical Journal, vol. 40, pp. 3-17, 2008.

[18]        F. Taghavi, M. Habibi-Rezaei, M. Amani, A. Saboury, and A. Moosavi-Movahedi, "The status of glycation in protein aggregation," International Journal of Biological Macromolecules, vol. 100, pp. 67-74, 2016.

[19]        T. Koschinsky, C.-J. He, T. Mitsuhashi, R. Bucala, C. Liu, C. Buenting, K. Heitmann, and H. Vlassara, "Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy," Proceedings of the National Academy of Sciences, vol. 94, pp. 6474-6479, 1997.Available at: https://doi.org/10.1073/pnas.94.12.6474.

[20]        R. D. Semba, E. J. Nicklett, and L. Ferrucci, "Does accumulation of advanced glycation end products contribute to the aging phenotype?," Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, vol. 65, pp. 963-975, 2010.Available at: https://doi.org/10.1093/gerona/glq074.

[21]        F. Mangialasche, M. Kivipelto, P. Mecocci, D. Rizzuto, K. Palmer, B. Winblad, and L. Fratiglioni, "High plasma levels of vitamin E forms and reduced Alzheimer's disease risk in advanced age," Journal of Alzheimer's Disease, vol. 20, pp. 1029-1037, 2010.Available at: https://doi.org/10.3233/jad-2010-091450.

[22]        G. W. Burton and M. G. Traber, "Vitamin E: antioxidant activity, biokinetics, and bioavailability," Annual Review of Nutrition, vol. 10, pp. 357-382, 1990.Available at: https://doi.org/10.1146/annurev.nutr.10.1.357.

[23]        M. J. Engelhart, M. I. Geerlings, A. Ruitenberg, J. C. van Swieten, A. Hofman, J. C. Witteman, and M. M. Breteler, "Dietary intake of antioxidants and risk of Alzheimer disease," Jama, vol. 287, pp. 3223-3229, 2002.Available at: https://doi.org/10.1001/jama.287.24.3223.

[24]        A. Cherubini, A. Martin, C. Andres-Lacueva, A. Di Iorio, M. Lamponi, P. Mecocci, B. Bartali, A. Corsi, U. Senin, and L. Ferrucci, "Vitamin E levels, cognitive impairment and dementia in older persons: The InCHIANTI study," Neurobiology of Aging, vol. 26, pp. 987-994, 2005.Available at: https://doi.org/10.1016/j.neurobiolaging.2004.09.002.

[25]        G. Ravaglia, P. Forti, A. Lucicesare, N. Pisacane, E. Rietti, F. Mangialasche, R. Cecchetti, C. Patterson, and P. Mecocci, "Plasma tocopherols and risk of cognitive impairment in an elderly Italian cohort–," The American Journal of Clinical Nutrition, vol. 87, pp. 1306-1313, 2008.Available at: https://doi.org/10.1093/ajcn/87.5.1306.

[26]        M. C. Morris, D. A. Evans, J. L. Bienias, C. C. Tangney, D. A. Bennett, N. Aggarwal, R. S. Wilson, and P. A. Scherr, "Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study," Jama, vol. 287, pp. 3230-3237, 2002.Available at: https://doi.org/10.1001/jama.287.24.3230.

[27]        F. Mangialasche, W. Xu, M. Kivipelto, E. Costanzi, S. Ercolani, M. Pigliautile, R. Cecchetti, M. Baglioni, A. Simmons, and H. Soininen, "Tocopherols and tocotrienols plasma levels are associated with cognitive impairment," Neurobiology of Aging, vol. 33, pp. 2282-2290, 2012.Available at: https://doi.org/10.1016/j.neurobiolaging.2011.11.019.

[28]        M. G. Traber, "Vitamin E inadequacy in humans: Causes and consequences," Advances in Nutrition, vol. 5, pp. 503-514, 2014.Available at: https://doi.org/10.3945/an.114.006254.

[29]        M. C. Morris, D. A. Evans, C. C. Tangney, J. L. Bienias, R. S. Wilson, N. T. Aggarwal, and P. A. Scherr, "Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change–," The American Journal of Clinical Nutrition, vol. 81, pp. 508-514, 2005.Available at: https://doi.org/10.1093/ajcn.81.2.508.

[30]        O. B. Usoro and S. A. Mousa, "Vitamin E forms in Alzheimer's disease: A review of controversial and clinical experiences," Critical Reviews in Food Science and Nutrition, vol. 50, pp. 414-419, 2010.Available at: https://doi.org/10.1080/10408390802304222.

[31]        M. C. Morris, J. A. Schneider, H. Li, C. C. Tangney, S. Nag, D. A. Bennett, W. G. Honer, and L. L. Barnes, "Brain tocopherols related to Alzheimer's disease neuropathology in humans," Alzheimer's & Dementia, vol. 11, pp. 32-39, 2015.Available at: https://doi.org/10.1016/j.jalz.2013.12.015.

[32]        P. P. Zandi, J. C. Anthony, A. S. Khachaturian, S. V. Stone, D. Gustafson, J. T. Tschanz, M. C. Norton, K. A. Welsh-Bohmer, and J. C. Breitner, "Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: The cache county study," Archives of Neurology, vol. 61, pp. 82-88, 2004.Available at: https://doi.org/10.1001/archneur.61.1.82.

[33]        M. M. Essa, R. K. Vijayan, G. Castellano-Gonzalez, M. A. Memon, N. Braidy, and G. J. Guillemin, "Neuroprotective effect of natural products against Alzheimer’s disease," Neurochemical Research, vol. 37, pp. 1829-1842, 2012.Available at: https://doi.org/10.1007/s11064-012-0799-9.

[34]        J. A. Joseph, B. Shukitt-Hale, and L. M. Willis, "Grape juice, berries, and walnuts affect brain aging and behavior," The Journal of Nutrition, vol. 139, pp. 1813S-1817S, 2009.Available at: https://doi.org/10.3945/jn.109.108266.

[35]        E. E. Devore, J. H. Kang, M. M. Breteler, and F. Grodstein, "Dietary intakes of berries and flavonoids in relation to cognitive decline," Annals of Neurology, vol. 72, pp. 135-143, 2012.Available at: https://doi.org/10.1002/ana.23594.

[36]        R. Krikorian, T. A. Nash, M. D. Shidler, B. Shukitt-Hale, and J. A. Joseph, "Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment," British Journal of Nutrition, vol. 103, pp. 730-734, 2010.Available at: https://doi.org/10.1017/s0007114509992364.

[37]        B. A. Kase, H. Northrup, A. C. Morrison, C. M. Davidson, A. M. Goiffon, J. M. Fletcher, K. K. Ostermaier, G. H. Tyerman, and K. S. Au, "Association of copper-zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes with nonsyndromic myelomeningocele," Birth Defects Research Part A: Clinical and Molecular Teratology, vol. 94, pp. 762-769, 2012.Available at: https://doi.org/10.1002/bdra.23065.

[38]        B. R. Cardoso, T. P. Ong, W. Jacob-Filho, O. Jaluul, M. I. d. Á. Freitas, and S. M. F. Cozzolino, "Nutritional status of selenium in Alzheimer's disease patients," British Journal of Nutrition, vol. 103, pp. 803-806, 2010.Available at: https://doi.org/10.1017/s0007114509992832.

[39]        C. M. Quinzii and M. Hirano, "Coenzyme Q and mitochondrial disease," Developmental Disabilities Research Reviews, vol. 16, pp. 183-188, 2010.Available at: https://doi.org/10.1002/ddrr.108.

[40]        M. Bentinger, M. Tekle, and G. Dallner, "Coenzyme Q–biosynthesis and functions," Biochemical and Biophysical Research Communications, vol. 396, pp. 74-79, 2010.Available at: https://doi.org/10.1016/j.bbrc.2010.02.147.

[41]        D. J. Bonda, X. Wang, G. Perry, A. Nunomura, M. Tabaton, X. Zhu, and M. A. Smith, "Oxidative stress in Alzheimer disease: A possibility for prevention," Neuropharmacology, vol. 59, pp. 290-294, 2010.Available at: https://doi.org/10.1016/j.neuropharm.2010.04.005.

[42]        X. Yang, Y. Yang, G. Li, J. Wang, and E. S. Yang, "Coenzyme Q10 attenuates ß-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation," Journal of Molecular Neuroscience, vol. 34, pp. 165-171, 2008.Available at: https://doi.org/10.1007/s12031-007-9033-7.

[43]        M. J. Pletcher, K. Bibbins-Domingo, K. Liu, S. Sidney, F. Lin, E. Vittinghoff, and S. B. Hulley, "Nonoptimal lipids commonly present in young adults and coronary calcium later in life: the CARDIA (Coronary Artery Risk Development in Young Adults) study," Annals of Internal Medicine, vol. 153, pp. 137-146, 2010.Available at: https://doi.org/10.7326/0003-4819-153-3-201008030-00004.

[44]        M. L. Fernandez and K. L. West, "Mechanisms by which dietary fatty acids modulate plasma lipids," The Journal of Nutrition, vol. 135, pp. 2075-2078, 2005.Available at: https://doi.org/10.1093/jn/135.9.2075.

[45]        J. C. Kovacic, J. M. Castellano, and V. Fuster, "The links between complex coronary disease, cerebrovascular disease, and degenerative brain disease," Annals of the New York Academy of Sciences, vol. 1254, pp. 99-105, 2012.Available at: https://doi.org/10.1111/j.1749-6632.2012.06482.x.

[46]        Y. Gu, J. W. Nieves, Y. Stern, J. A. Luchsinger, and N. Scarmeas, "Food combination and Alzheimer disease risk: A protective diet," Archives of Neurology, vol. 67, pp. 699-706, 2010.Available at: https://doi.org/10.1001/archneurol.2010.84.

[47]        M. C. Morris, D. A. Evans, J. L. Bienias, C. C. Tangney, D. A. Bennett, N. Aggarwal, J. Schneider, and R. S. Wilson, "Dietary fats and the risk of incident Alzheimer disease," Archives of Neurology, vol. 60, pp. 194-200, 2003.Available at: https://doi.org/10.1001/archneur.60.2.194.

[48]        M. Kivipelto, E.-L. Helkala, M. P. Laakso, T. Hänninen, M. Hallikainen, K. Alhainen, S. Iivonen, A. Mannermaa, J. Tuomilehto, and A. Nissinen, "Apolipoprotein E ?4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease," Annals of Internal Medicine, vol. 137, pp. 149-155, 2002.Available at: https://doi.org/10.7326/0003-4819-137-3-200208060-00006.

[49]        C. Reitz, M.-X. Tang, N. Schupf, J. J. Manly, R. Mayeux, and J. A. Luchsinger, "Association of higher levels of high-density lipoprotein cholesterol in elderly individuals and lower risk of late-onset Alzheimer disease," Archives of Neurology, vol. 67, pp. 1491-1497, 2010.Available at: https://doi.org/10.1001/archneurol.2010.297.

[50]        M. O. Grimm, H. S. Grimm, I. Tomic, K. Beyreuther, T. Hartmann, and C. Bergmann, "Independent inhibition of Alzheimer disease ß-and ?-secretase cleavage by lowered cholesterol levels," Journal of Biological Chemistry, vol. 283, pp. 11302-11311, 2008.Available at: https://doi.org/10.1074/jbc.m801520200.

[51]        J. Popp, P. Lewczuk, H. Kölsch, S. Meichsner, W. Maier, J. Kornhuber, F. Jessen, and D. Lütjohann, "Cholesterol metabolism is associated with soluble amyloid precursor protein production in Alzheimer's disease," Journal of Neurochemistry, vol. 123, pp. 310-316, 2012.Available at: https://doi.org/10.1111/j.1471-4159.2012.07893.x.

[52]        E. Ernst and M. Pittler, "Ginkgo biloba for dementia," Clinical Drug Investigation, vol. 17, pp. 301-308, 1999.

[53]        S. Bastianetto, C. Ramassamy, S. Doré, Y. Christen, J. Poirier, and R. Quirion, "The ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced byß-amyloid," European Journal of Neuroscience, vol. 12, pp. 1882-1890, 2000.Available at: https://doi.org/10.1046/j.1460-9568.2000.00069.x.

[54]        M. Canevelli, N. Adali, E. Kelaiditi, C. Cantet, P.-J. Ousset, and M. Cesari, "Effects of Gingko biloba supplementation in Alzheimer's disease patients receiving cholinesterase inhibitors: Data from the ICTUS study," Phytomedicine, vol. 21, pp. 888-892, 2014.Available at: https://doi.org/10.1016/j.phymed.2014.01.003.

[55]        M. Dhanasekaran, L. A. Holcomb, A. R. Hitt, B. Tharakan, J. W. Porter, K. A. Young, and B. V. Manyam, "Centella asiatica extract selectively decreases amyloid ß levels in hippocampus of Alzheimer's disease animal model," Phytotherapy Research, vol. 23, pp. 14-19, 2009.Available at: https://doi.org/10.1002/ptr.2405.

[56]        M. V. Kumar and Y. Gupta, "Effect of different extracts of Centella asiatica on cognition and markers of oxidative stress in rats," Journal of Ethnopharmacology, vol. 79, pp. 253-260, 2002.Available at: https://doi.org/10.1016/s0378-8741(01)00394-4.

[57]        O. Dev and R. Dev, "Comparison on cognitive effects of Centella asiatica in healthy middle age female and male volunteers," Annals of Nutrition and Metabolism, vol. 55, pp. 709-709, 2009.

[58]        S. Tiwari, S. Singh, K. Patwardhan, S. Gehlot, and I. Gambhir, "Effect of Centella asiatica on mild cognitive impairment (MCI) and other common age-related clinical problems," Digest Journal of Nanomaterials and Biostructures, vol. 3, pp. 215-220, 2008.

[59]        A. J. Mitchell and M. Shiri-Feshki, "Rate of progression of mild cognitive impairment to dementia–meta-analysis of 41 robust inception cohort studies," Acta Psychiatrica Scandinavica, vol. 119, pp. 252-265, 2009.Available at: https://doi.org/10.1111/j.1600-0447.2008.01326.x.

Views and opinions expressed in this article are the views and opinions of the author(s), Journal of Brain Sciences shall not be responsible or answerable for any loss, damage or liability etc. caused in relation to/arising out of the use of the content.