Alzheimer's disease in Vitamin D Points of view

 Kyle J. Norton(Draft Article)

Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.
Vitamin D is a fat-soluble secosteroids found in small amount in few foods, including salmon, mackerel, sardines and tuna. The vitamin plays an important role in modulation of cellular proliferation, apoptosis induction, tumor growth suppression and promotion in absorption of minerals, including calcium, iron, magnesium, phosphate and zinc.

1. Vitamin D receptors(VDR)
Vitamin D receptors, also known as NR1I1 (nuclear receptor subfamily 1, group I, member 1), with functions of regulation in many metabolic pathways, including cancers, plays an important role in risk of Alzheimers' disease. Polymorphisms in the vitamin D receptor (VDR), and insufficient serum 25 hydroxyvitamin D₃ levels patients have been found to association with age- dependent cognitive decline(1). The study of Vitamin D(3), a neurosteroid that mediates its effects via the vitamin D receptor (VDR) also indicated  a possible link between AD and certain VDR polymorphisms ijn early onset of  AD(2) through suppression of VDR by Aβ(3). Treatment of Vitamin D was found effectively in inhibition of Aβ induced alterations in primary cortical neurons(4). The Istanbul University in study of the association of between VDR gene and late-onset Alzheimer's disease (AD) with 104 cases of dementia of Alzheimer type and 109 age-matched controls, showed an significant increased Aa genotype in AD patient than health individuals with the same genotype, of that may be an indication of "Aa" genotype may be associated to increased risk of developing AD. In the comparison of "AA" genotype, risk of AD in men with Aa genotyes  are 2.3 times higher(5).

2, Plasma of vitamin D
Suggestion of serum levels of vitamin D used as diagnosis for indication of early onset of Alzheimer's' diseases may be controversial. Some researcher suggested that lower plasma nutrient levels  only a indication for impaired systemic availability of several nutrients in AD(6). The Kingston University study showed level of 25hydroxyvitamin D (25OHD) was found to be lower in patients with the disease, arising from extremely low levels of 25OHD2 along with low levels of 25OHD3.(7). In the study of the correlation of Alzheimer's disease and osteoporosis, the Heinrich-Heine-University showed that 25 (OH) vitamin D plasma levels were low normal and of equal amount in all groups except for the osteoporosis group(8).

The benefits
Epidemiological studies, focusing vitamin D and its derivative in reduced risk of Alzheimer's diseases have not been consistent. Researchers at the indicated that Gene polymorphisms alternation of vitamin D metabolism are also associated with a higher incidence or a worse disease prognosis, and despite the links between vitamin D deficiency and the risks of developing neurological disorders, there is, to date, no proof that supplementation could alter the course of these diseases(9)
Study of the effects of vitamin D showed an indication of prevention of neurons cytotoxicity and apoptosis through downregulating  LVSCC A1C(L-type voltage-sensitive calcium channel with function of gene expression, synaptic efficacy, and cell survival) and upregulating VDR and balancing nerve growth factor (NGF) expressions(10). Researchers at the ¹Vietnamese American Medical Research Foundation, suggested that vitamin D supplements appeared beneficial to patients of AD through many mechanisms including regulating micro-RNA, enhancing toll-like receptors, modulating vascular endothelial factor expression, modulating angiogenin, and advanced glycation end products, etc.(1i). The combination of memantine with vitamin D, a neurosteroid hormone, in the joint study, showed an evidence lesser cortical axons degeneration after exposure to amyloid-beta peptide or glutamate in microfluidic neuronal cultures.(12). Unfortunately, regardless to the effectiveness of vitamin D in reduced risk of cognitive impairment or Aβ, many researchers still believed that there is no truly effective therapy has been developed for Alzheimer's disease or mild cognitive impairment(13).

Taking altogether, without going into reviews, vitamin D may be considered as a therapeutic treatment in reduced risk of Alzheimers' diseases, through many mechanisms, including induction of Aβ, regulation of micro-RNA expression, etc.. Over doses of vitamin D supplement may cause excessive calcium absorption, calcification, Urinary stones etc. please make sure to follow the guideline of the Institute of Medicine of the National Academies.

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Back to Kyle J. Norton Home page http://kylejnorton.blogspot.ca References
(1) A novel perspective for Alzheimer's disease: vitamin D receptor suppression by amyloid-β and preventing the amyloid-β induced alterations by vitamin D in cortical neurons by Dursun E¹, Gezen-Ak D, Yilmazer S.(PubMed)
(2) Vitamin D receptor gene haplotype is associated with late-onset Alzheimer's disease.

Gezen-Ak D¹, Dursun E, Bilgiç B, Hanağasi H, Ertan T, Gürvit H, Emre M, Eker E, Ulutin T, Uysal O, Yilmazer S.(PubMed)
(3) A new mechanism for amyloid-β induction of iNOS: vitamin D-VDR pathway disruption by Dursun E¹, Gezen-Ak D, Yilmazer S(PubMed)
(4) A novel perspective for Alzheimer's disease: vitamin D receptor suppression by amyloid-β and preventing the amyloid-β induced alterations by vitamin D in cortical neurons by Dursun E¹, Gezen-Ak D, Yilmazer S(PubMed)

(5) Association between vitamin D receptor gene polymorphism and Alzheimer's disease.

Gezen-Ak D¹, Dursun E, Ertan T, Hanağasi H, Gürvit H, Emre M, Eker E, Oztürk M, Engin F, Yilmazer S.(PubMed)
(6) Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis by Lopes da Silva S¹, Vellas B, Elemans S, Luchsinger J, Kamphuis P, Yaffe K, Sijben J, Groenendijk M, Stijnen T.(PubMed)
(7) Low 25OH vitamin D2 levels found in untreated Alzheimer's patients, compared to acetylcholinesterase-inhibitor treated and controls by Shah I¹, Petroczi A, Tabet N, Klugman A, Isaac M, Naughton DP.(PubMed)
(8) Blood biomarkers of osteoporosis in mild cognitive impairment and Alzheimer's disease by Luckhaus C¹, Mahabadi B, Grass-Kapanke B, Jänner M, Willenberg H, Jäger M, Supprian T, Fehsel K.(PubMed)
(9) [Vitamin D and neurology].[Article in French] by Thouvenot ɹ, Camu W(PubMed)

(10) The Effects of Vitamin D Receptor Silencing on the Expression of LVSCC-A1C and LVSCC-A1D and the Release of NGF in Cortical Neurons by Duygu Gezen-Ak, Erdinç Dursun, and Selma Yilmazer(PubMed)
(11) The role of vitamin D in Alzheimer's disease: possible genetic and cell signaling mechanisms by Lu'o'ng KV¹, Nguyen LT.(PubMed)
(12) Combination of memantine and vitamin D prevents axon degeneration induced by amyloid-beta and glutamate by Annweiler C¹, Brugg B, Peyrin JM, Bartha R, Beauchet O(PubMed)

Alzheimer's disease in Vitamin C Points of view

 Kyle J. Norton(Draft Article)

Alzheimer's disease is a brain disorder correlated with major reductions in the addition of new neurons to the respective target areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.
Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin, found in fresh fruits, berries and green vegetables. It is best known for its free radical scavengers activity and regenerating oxidized vitamin E for immune support.

Epidemiological studies linking vitamin C in reduced risk of Alzheimers' disease may be inconclusive. 
But some researchers in the survey of Alzheimers' patients found inadequate dietary vitamin C due to low intake of vegetables and fruits(1). The study from Vanderbilt University Medical Center showed a positive effect in maintaining healthy vitamin C levels enhanced  protective function against age-related cognitive decline and Alzheimer's disease, but avoiding vitamin C deficiency would be more beneficiary than taking supplements(2). On the basis of the meta-analysis studies published up to October 2011 between in Medline and Scopus databases, dietary intakes of the three antioxidants (vitamin E, vitamin C, and β-carotene) can lower the risk of AD(3). Vitamin complex included ascorbic acid, alpha-tocopherol, and beta-carotene, showed to reduce oxidative stress in PBMNC of AD patients through lowering ROS (Reactive oxygen species)  production, improved cellular antioxidant capacities and modified cytokine induced inflammation(4). Aβ42 aggregation induced neurotoxicity, causing synaptic dysfunction and  induced tissue oxidation (DNA/RNA, proteins, and lipids) through trace metals may be inhibited by antioxidants such as vitamin C through conversion of toxic superoxide radical to less reactive hydrogen peroxide, contributing to protection from AD(5). Other suggested that since intracellular ascorbate serves several functions in the CNS, including antioxidant protection, peptide amidation, myelin formation, synaptic potentiation, and protection against glutamate toxicity, it may protect neurons from the oxidant damage associated with neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's(6). Unfortunately, in Oral supplementation of vitamin C and vitamin E therapy against Alzheimers' disease conducted by Auburn University detected no difference in the incidence of AD during the 4-year follow-up, and suggested vitamin C should not be recommended due to  lack of consistent efficacy data of vitamin C in preventing or treating AD(7)(8) and a cross-sectional study, plasma Aβ40 and Aβ42 and dietary data obtained from 1,219 cognitively healthy elderly with age >65 years, found no association of vitamins complex correlated with plasma Aβ levels(9).

Taking altogether, composition of vitamin complex included vitamin C may be effective in reduced risk of Alzheimers' disease and treatment through protection of neurons from oxidative damage, against glutamate toxicity, etc. Daily ingestion of high-dose vitamin C may be considered safe, but in rare incidence, overdoses in a prolonged period of time, may cause intra-renal oxalate crystal deposition, a fatal nephrotoxicity(10)(11).

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References
(1) Dietary fat and antioxidant vitamin intake in patients of neurodegenerative disease in a rural region of Jalisco, Mexico by Navarro-Meza M, Gabriel-Ortiz G, Pacheco-Moisés FP, Cruz-Ramos JA, López-Espinoza A.(PubMed) 
(2) A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease by Harrison FE.(PubMed)
(3) Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis by Li FJ¹, Shen L, Ji HF.(PubMed)
(4) Ascorbic acid, alpha-tocopherol, and beta-carotene reduce oxidative stress and proinflammatory cytokines in mononuclear cells of Alzheimer's disease patients by de Oliveira BF, Veloso CA, Nogueira-Machado JA, de Moraes EN, Santos RR, Cintra MT, Chaves MM.(PubMed)
(5) Formation of the 42-mer Amyloid β Radical and the Therapeutic Role of Superoxide Dismutase in Alzheimer's Disease by Murakami K¹, Shimizu T, Irie K.(PubMed)
(6) Vitamin C transport and its role in the central nervous system by May JM.(PubMed)



(7)Vitamin C and vitamin E for Alzheimer's disease by Boothby LA¹, Doering PL.(PubMed) 
(8) Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer's disease by Arlt S¹, Müller-Thomsen T, Beisiegel U, Kontush A.(PubMed)
(9) Nutrient intake and plasma β-amyloid by Gu Y¹, Schupf N, Cosentino SA, Luchsinger JA, Scarmeas N.(PubMed)

(10) Fatal vitamin C-associated acute renal failure by McHugh GJ, Graber ML, Freebairn RC.(PubMed)

(11) Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis by Urivetzky M, Kessaris D, Smith AD.(PubMed)

Alzheimer's disease in Vitamin A Points of view

 Kyle J. Norton(Draft Article)

Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas through destruction of brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease.

Vitamin A is a general term of Vitamin A Retinol, retinal, beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin best known for its functions for vision health and antioxidant scavenger and essential for growth and differentiation of a number of cells and tissues.
Recommended intakes of vitamin A, according to the Institute of Medicine of the National Academies (formerly National Academy of Sciences) is 600 µg daily as extremely high doses (>9000 mg) can be toxicity, causing dry, scaly skin, fatigue, nausea, loss of appetite, bone and joint pains, headaches, etc.
1. Retinols
Retinoids, derived from Vitamin A involve in cellular regulatory processes including cell differentiation, neurite outgrowth and defense against oxidative stress. In patients with Alzheimers; disease, plasma levels including retinols was found to be sgnificantly lower of that may suggested the vascular comorbidities of patients with AD may be result of certain degrees of depletion of the antioxidant defense system(1). The study of Kanazawa University Graduate School of Medical Science, indicated that vitamin A (retinol, retinal and retinoic acid) inhibited the formation, extension and destabilizing effects of β-amyloid fibrils and  the oligomerization of Aβ (Aβ40 and Aβ42)(2) and Aβ1-16 and Aβ25-35(3). According to University Hospitals Case Medical Center, Retinoids may influence Amyloid beta processing upregulation of alpha secretase via ADAM10 and inhibit formation of Amyloid fibrils(4) with these properties of retinoids are relevant to theories of Alzheimer's disease pathogenesis.
Retinoic acid receptor (RAR) α systemactivated by both all-trans retinoic acid and 9-cis retinoic acid sginalling is found downreguated by amyloid beta (Aβ) in Alzheimers patients. There fore stimulation of the RARα signalling pathway using a synthetic agonist may be effective reverse the the cognitive impairment caused by amyloid beta (Aβ)(5). In Streptozotocin (STZ) induced mice, all-trans-retinoic acid (ATRA) treatment significantly attenuated STZ-induced memory deficits, biochemical and histopathological alterations(6).

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, play an important role in prevention and treatment of some diseases through it antioxidant effects.
The study of Plasma Levels of HDL and Carotenoids in Alzheimer's patients indicated the protective effects of elevating HDL alone compared with elevating carotenoids alone or elevating both to reduce risk for dementia(7). The study of Rayalaseema University, Kurnool, Andhra Pradesh showed the anti oxidant effects of carotenoids in reduced symptoms of Alzheimer's diseases through inhibition of amyloid beta (Aβ) formation, deposition and fibril(8). Plasma of carotenoids may be used as a marker to determine the severity of AD. According to Oregon Health and Science University, there was an association between higher carotenoids levels and DHA and higher MMSE (tests that screen for Alzheimer's,)scores, supports a protective role of both types of nutrients in AD(9)(10). In a in the community-dwelling elderly study indicated that use of supplemental antioxidants (vitamins A, C, or E, plus selenium or zinc) is associated with reduction of cognitive decline(11) with vitamin A is found to be destabilization of beta-amyloid fibrils (fAbeta)(12).

Taking altogether, plasma levels of vitamin A may be an indication of marker in identification of the early onset of Alzheimer's disease which may be beneficiary with the intake of vitamin A, regardless to its forms. Overdoses can lead to toxic symptoms. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.

References
(1) [Influence of vascular comorbidities on the antioxidant defense system in Alzheimer's disease].

[Article in German by Polidori MC¹, Stahl W, De Spirt S, Pientka L(PubMed)

(2) Vitamin A and Alzheimer's disease by Ono K¹, Yamada M.(PubMed)
(3) Vitamin A has anti-oligomerization effects on amyloid-β in vitro by Takasaki J¹, Ono K, Yoshiike Y, Hirohata M, Ikeda T, Morinaga A, Takashima A, Yamada M(PubMed)

(4) Retinoids for treatment of Alzheimer's disease by Lerner AJ¹, Gustaw-Rothenberg K, Smyth S, Casadesus G(PubMed)
(5) Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist by Goncalves MB¹, Clarke E, Hobbs C, Malmqvist T, Deacon R, Jack J, Corcoran JP(PubMed)
(6) All-trans retinoic acid rescues memory deficits and neuropathological changes in mouse model of streptozotocin-induced dementia of Alzheimer's type by Sodhi RK¹, Singh N.(PubMed)
(7) Plasma Levels of HDL and Carotenoids are Lower in Dementia Patients with Vascular Comorbidities by Dias IH¹, Polidori MC², Li L¹, Weber D³, Stahl W⁴, Nelles G⁵, Grune T³, Griffiths HR¹.(PubMed)
(8) Carotenoids and Alzheimer's disease: an insight into therapeutic role of retinoids in animal models by Obulesu M¹, Dowlathabad MR, Bramhachari PV.(PubMed)
(9) Nutritional biomarkers in Alzheimer's disease: the association between carotenoids, n-3 fatty acids, and dementia severity by Wang W¹, Shinto L, Connor WE, Quinn JF.(PubMed)
(10) Plasma levels of antioxidants are not associated with Alzheimer's disease or cognitive decline by Engelhart MJ¹, Ruitenberg A, Meijer J, Kiliaan A, van Swieten JC, Hofman A, Witteman JC, Breteler MM.(PubMed)
(11) Is antioxidant use protective of cognitive function in the community-dwelling elderly? by Gray SL¹, Hanlon JT, Landerman LR, Artz M, Schmader KE, Fillenbaum GG.(PubMed)
(12) Vitamin A exhibits potent antiamyloidogenic and fibril-destabilizing effects in vitro by Ono K¹, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M.(PubMed)

Alzheimer's disease In Herbs' Points of View

Alzheimer's disease is a brain disorder correlated with major reductions in the addition of new neurons to the respective target areas and named after German physician Alois Alzheimer. Alzheimer's destroys brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal. 
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's diseas. It may be results of  cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions) and the possible beneficial roles of psychosocial factors (eg, high education, active social engagement, physical exercise, and mentally stimulating activity)(1) Strong evidences emerged in epidemiological studies suggested that certain herbs(2) may have potential in reduced risk and treatments of Alzheimer's disease but geographic source of the plant material, climatation, and time of harvest may effect their effectiveness. It is understandable that commercially available herbal medicinal products with the same herbal ingredients vary in their content and concentration of chemical constituents when compared between manufacturers.

1. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It Has been used in traditional herbal medicine in treating impotence, memory loss,respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
 Extracts of the leaves of the maidenhair tree, Ginkgo biloba, in identified trails on 26 June 2002 through a search of the CDCIG Specialized Register which contains records from all main medical databases, showed a positive effect of Ginkgo biloba in improvement of cognition and function(3). Study from Hospital St. Naum, Sofia, in enrolled 96 outpatients, aged 50 years or above, who met the NINCDS/ADRDA criteria for probable AD, showed no significance effect in either EGb 761(R)(Ginkgo biloba extract) and donepezil, but the result of the combination of 2 both substances are efficacy in treatment in patients with AD and neuropsychiatric features(4). But in the study of the same extract, Maria-Hilf Hospital Krefeld, Krefeld indicated that EGb 761® improved cognitive functioning, neuropsychiatric symptoms and functional abilities in both types of dementia namely Alzheimer's disease and vascular dementia(5)(6).

2. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root).
In in an open-label study, conducted by Seoul National University Hospital, Ginseng improved ADAS and MMSE scores declined and may be considered as clinically effective in the cognitive performance of AD patients(7). Other study also showed the effect of KRG on cognitive functions which was sustained for 2 yr follow-up and may be an indication of  a feasible efficacies of long-term follow-up for Alzheimer's disease(9). Korean red ginseng (KRG) in high doses, significant improved on the ADAS and CDR after 12 weeks(8). Unfortunately, Study by the Korea Institute of Oriental Medicine, on Mini-Mental Status and the Alzheimer's Disease Assessment Scale (ADAS)-cognitive, showed inconclusive in the result of the efficacy of Ginseng(10).

3. Gotu Kola
Gotu Kola also known as centella, is a annual plant of the genus, belonging to the family Mackinlayaceae, native to India, Sri Lanka, northern Australia, Indonesia, Iran, Malaysia, Melanesia, Papua New Guinea. The herb has been used in traditional medicine to treat nervous disorders, epilepsy, senility, premature aging, etc.
Centella asiatica (CA), commonly named gotu kola water extract of CA (GKW), in the Tg2576 mouse, a murine model of AD with high β-amyloid burden, showed to attenuated β-amyloid-associated behavioral abnormalities in these mice and protected SH-SY5Y cells and MC65 human neuroblastoma cells from toxicity(11) through the impact of the amyloid cascade altering amyloid beta pathology(12) and colchicine-induced memory impairment and oxidative damage(13).

4. Lemon Balm
Lemon Balm is is a perennial plant in the genus Melissa, belonging to the family Lamiaceae, native to southern Europe and the Mediterranean region. The herb has been used in traditional medicine to treat nervous complaints, lower abdominal disorders and as anti-inflammatory, antivirus, antibacterial agent.
 Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy(14). In a study of 20 healthy, young participants received single doses of 600, 1000, and 1600 mg of encapsulated dried leaf at 7-day intervals, indicated that doses of Melissa officinalis at or above the maximum employed here can improve cognitive performance and mood(15). Other study of a standardized M. officinalis extract (300 mg, 600 mg), indicated a significantly increased self-ratings of calmness and reduced self-ratings of alertness and negated the negative mood effects of the DISS(16)(17).

5. Rosemary
Rosemary is a perennial herb with fragrant, evergreen, needle-like leaves, the genus Rosmarinus, belonging to the family Lamiaceae. Its fresh and dried leaves has been used frequently in traditional Mediterranean cuisine and as flavor foods while barbecuing. Rosnary has been used in traditional medicine as an antiseptic, antioxidant, and antispasmodic agent to treat circulatory problem, eczema, rheumatism, muscle pain, etc.
Carnosic acid (CA), a chemical compound found in rosemary and sage, reduces Aβ production, at least partially, by activating TACE in human astroglial cells(18) and  the University of Tlemcen, also indicated that CA may be potential against Acetylcholinesterase (AChE) which gradual and irreversible declines in cognitive functions in AD patients(19). In an aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening, showed that the combination may have some potential for improving cognitive function, especially in AD patients(20).

6. Chinese Cat's claw 
Chinese Cat's claw also known as Gou Teng, Uncaria rhynchophylla, a genus of Uncaria, belonging to the family Rubiaceae, native to China. The herb is said to consist neuroprotective, anticonvulsive, sedative and antipsychotic effect.
Mice given a subcutaneous injection of D-gal (50 mg/kg) and orally administered  Uncaria rhynchophylla (EUR) (100, 200, or 400 mg/kg) daily for 8 weeks, significantly increased exploratory behavior (assessed by an open-field test) and improved spatial learning and memory function (assessed by the Morris water maze test) as well as increasing the levels of acetylcholine and glutathione and decreasing the activity of acetylcholinesterase and the level of malondialdehyde in the brains through enhancement of the antioxidant status of brain tissue(21. Center for Asian Traditional Medicine Research, Tohoku University also indicated that Uncaria rhynchophylla has remarkably inhibitory effects on the regulation of Abeta fibrils(22), a significant step in the pathogenesis of Alzheimer's disease. 

7. Polygala tenuifolia
 Polygala tenuifolia also known as Yuan Zhi is a genus Polygala, belonging to family Polygalaceae, native to China. The herb has been used in TCM to insomnia, forgetfulness, emotional and disorientation with abundance of phlegm, seizures, anxiety, listlessness, boils, abscesses, sores,etc.
Extract of dried root of Polygala tenuifolia Willdenow was found to provide some protective effects against neuronal death and cognitive impairments in Alzheimer's disease (AD), in the study bythe Seoul National University(23). Tenuigenin, a crude extract of Polygala tenuifolia Willd. significantly decreased Abeta secretion from COS-7 cells without altering the ratio of Abeta1-40 and Abeta-42 (in differentiation of change in Abeta metabolism) probably through inhibition of the deposit of beta-site APP cleaving enzyme(causing increased levels of amyloid beta (Abeta) peptide, an early and critical feature of Alzheimer's disease)(24) or inhibited the secretion of A beta in SH-SY5Y APP 695 cells (amyloid precursor protein (APP)) via BACE1 inhibition(reduced risk of the build up of beta-amyloid and slow or stop Alzheimers disease)(25). Ninjin-yoei-to (NYT; Ren-shen-yang-rong-tang in Chinese formula, among 14 kinds of component herbs in NYT, the roots of Polygala tenuifolia  extracts increased nerve growth factor NGF levels from the astrocytes(star shaped glial cells with function of support to neurons and clean up debris within the brain)(26).

8. Salvia officinalis (Sage)
Sage is a ornamental plant of the genus Salvia, belonging to family Lamiaceae, native to the Central and South America, Central, Eastern Asia and Mediterranean. The herb has been used in traditional medicine as carminative, antiperspirant, antispasmodic, astringent, antiseptic, and antibiotic agent and to calm the central nervous system, treat spasms in smooth and skeletal muscles, relieve digestive problems, regulate menstruation, etc.
According to the Northumbria University, extracts Salvia officinalis exerted its anti-oxidant, estrogenic, anti-inflammatory properties, and specifically inhibited butyryl- and acetyl-cholinesterase (to prevent impeded neurotransmission)(27). Rosmarinic acid from Sage, in mild to moderate Alzheimer's disease (AD), enhanced the neuroprotective effect of sage against Abeta-induced toxicity, through inhibition of reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation(cell apoptosis), and tau protein hyperphosphorylation(neurofibrillary degeneration)(28)

9. Papaver somniferum (Opium poppy)
Papaver somniferum is a genus of Papaver, belonging to the family Papaveraceae, native to the Mediterranean Basin, Southeastern Europe, and Western Asia. The herb has been used in folk medicine for treating asthma, stomach illnesses, and bad eyesight.
Opium poppy exerted it neuroprotective effect through interaction of alkaloid opioids of herb with endogenous opiate receptors in the brain, according to Medical Research Council, Newcastle General Hospital(29). Some alkaloids isolated from plants, or are derived from templates of compounds from plant sources have been in clinical use for treatment of cognitive disorders(30).

10. saffron (Crocus sativus) 
Saffron is a spice derived from the flower of Crocus sativus which is a genus Crocus, belonging to the family Iridaceae, native to Southeast Asia.
Saffron extract, showed moderate AChE inhibitory activity, verified by in silico docking studies(31) and some promising effects in clinical studies with dementia patients(32). In a double-blind, placebo-controlled Tehran University of Medical Science study, suggested a positive mild to moderate Alzheimer's disease effect through inhibition of the aggregation and deposition of amyloid β in the human brain(33). Crocin isolated from Saffron, in Alzheimer's disease induced by intracerebroventricular (icv) streptozocin (STZ) in male rats, significantly attenuated learning and memory impairment(34).

11. Bacopa  monnieri
Bacopa  monnieri  is a genus Bacopa, belonging to family Plantaginaceae, native to the wetlands of southern India and Australia. The herb has been used in Indian traditional medicine as a neurological tonic and cognitive enhancer.
In intracerebroventricular administration of colchicine induced cognitive impairment in rats, Bacopa  monnieri decreased in activity of antioxidant enzyme, reversed memory impairment and altered activity of membrane bound enzymes(35). Other study of Bacopa monnieri extract indicated an improvement of   the escape latency time (p<.01) in Morris water maze test with reduction of neurons and cholinergic neuron densities were also mitigated(36). Researchers at the suggested that Bacopa monnieri may be effective in improving memory performance and exerted protective effects against AD by increasing expression or activity of Na⁺, K⁺-ATPase.Na⁺-K⁺-ATPase which plays an important role in AD, and may be a potent neuroprotective modulator against AD(37).

12. Alpinia galanga
Alpinia galanga is the genus Alpinia, belonging to the family Zingiberaceae, native to Indonesia and South Asia. The herb has been used in folk medicine in treating arthritis and rheumatoid arthritis, relieving discomfort caused due to inflammation of the abdomen and ulcers, etc.
On oxidative stress induced Alzheimer's type amnesia in mice, Alphinia galanga attenuated the elevated levels of acetylcholinesterase and monoamine oxidase enzymes in amnesia induced mic(38) and acted as Acetylcholinesterase (AChE) inhibitors which are widely used for the treatment of Alzheimer's disease (AD)(39). The Lalitha College of Pharmacy study suggested that Alpinia galanga fractions increases habituation memory and decreased escape latency in Alzheimer's type of amnesia in mice induced by Aβ((25-35), through increment in Na(+)/K(+)-ATPase and antioxidant activity depicts brain membrane integrity improvement and free radical scavenging property(40).

13. Calabar bean
 Calabar bean is the seed of climbing perennial plant, a genus Physostigma, belonging to the family Fabaceae, native to the tropical Africa. The herb has been used in folk medicine in contract the pupil, manage ocular pressure in glaucoma, etc.
Physostigmine, a major alkaloids from Physostigma venenosum exhibited its neuroprotective affect in Alzheimers' disease through inhibition of acetyl- and butyrylcholinesterase (BChE) activities(41) and alleviated of AD pathology and associated symptoms, for cognitive and for behavioural and psychological symptoms of dementia (BPSD)(42). The University of Massachusetts study showed that Calabar bean in dose-response relationships, enhances memory, and improves drug discovery activities(42).

14. The Compositions
14.1. Yi-Gan San
Yi-Gan San also known as Yokukansanin Japan, is a Bupleurum Formula consisting Chai Hu,  Fu Ling,  Chuan Xiong, Gan Cao, Dang Gui, Gou Teng and Cang Zhu. The composition has been used in traditional Chinese medicine for treatment of calms impatience, difficulty falling asleep or staying asleep.
Yi-Gan San exhibited a clinically significant decrease in terms of hallucinations, agitation, anxiety, irritability or abnormal behavior(44)(45) and improved behavioral and psychological symptoms of dementia (BPSD) and activities of daily living (ADL)(46). In olfactory bulbectomized (OBX) mice, The composition reversed spatial working memory and non-spatial working memory impairments, through reversed OBX-induced down-regulation of choline acetyltransferase and muscarinic muscarinic M1 receptor expression without affecting muscarinic M₃ receptor expression or AChE activity(47). The Kanto Central Hospital study reported a case of 81 years of age patient with symptoms of metabolic alkalosis with hypokalemia, due to intake of Yokukansan for 6 months(48).

14.2.  Ba Wei Di Huang Wan (BDW)
Ba Wei Di Huang Wan (BDW) is also known as Rehmannia Eight Formula, cosisting, Chinese herbs Fu Zi, Rou Gui, Shu Di Huang, Shan Yao, Shan Zhu Yu, Mu Dan Bi, Fu Ling and Ze Xie. The formula has been used in traditional Chniese medicine in tonifying Kidney and enhancing kidney Qi.
In the search combined the terms Alzheimer disease, dementia, cognition disorders, Herbal, Phytotherapy, tthe composition found to be effective in treating cognitive impairment of AD(49). The Tohoku University suggested that Ba Wei Di Huang Wan (BDW) improved Cognitive function and activities of daily living (ADLs)(50).

Taking altogether, without going into reviews. the list of herbs above may be effective in alleviating symptoms and treating Alzheimer's disease through inhibition of of acetyl- and butyrylcholinesterase (BChE) activities. Some researchers suggested that the use of herbal medicines in the treatment of AD should be comparable to the pharmacological treatment currently in use, including the identification of the active ingredients in order to improve the validation of the clinical trial with large-scale, multicenter studies(51).

References
(1) Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. by Qiu C, Kivipelto M, von Strauss E.(PubMed)
(2) The Use of Herbal Medicine in Alzheimer's Disease—A Systematic Review by Leopoldo Luiz dos Santos-Neto,¹ Maria Alice de Vilhena Toledo,² Patrícia Medeiros-Souza,³ and Gustavo Almeida de Souza(PubMed)
(3) Ginkgo biloba for cognitive impairment and dementia by Birks J, Grimley EV, Van Dongen M.(PubMed)
(4) Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: a randomised, double-blind, exploratory trial by Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R; GINDON Study Group(PubMed)
(5) Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer's disease and vascular dementia: results from a randomised controlled trial by Ihl R, Tribanek M, Bachinskaya N; GOTADAY Study Group(PubMed)
(6) Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trialby Napryeyenko O, Borzenko I; GINDEM-NP Study Group(PubMed)
(7) Panax ginseng enhances cognitive performance in Alzheimer disease by Lee ST, Chu K, Sim JY, Heo JH, Kim M(PubMed)
(8) An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease by Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.(PubMed)
(9) Improvement of cognitive deficit in Alzheimer's disease patients by long term treatment with korean red ginseng by Heo JH, Lee ST, Oh MJ, Park HJ, Shim JY, Chu K, Kim M(PubMed)
(10) Ginseng for cognitive function in Alzheimer's disease: a systematic review by Lee MS, Yang EJ, Kim JI, Ernst E(PubMed)
(11) Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer's Disease: Investigation of a Possible Mechanism of Action by Soumyanath A, Zhong YP, Henson E, Wadsworth T, Bishop J, Gold BG, Quinn JF(PubMed)
(12) Neuroprotective Effects of Centella asiatica against Intracerebroventricular Colchicine-Induced Cognitive Impairment and Oxidative Stress by Kumar A, Dogra S, Prakash A(PubMed)
(13) Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer's disease animal model by Dhanasekaran M, Holcomb LA, Hitt AR, Tharakan B, Porter JW, Young KA, Manyam BV(PubMed)
(14) Effect of aromatherapy on patients with Alzheimer's disease by Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K(PubMed)
(15) Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties by Kennedy DO, Wake G, Savelev S, Tildesley NT, Perry EK, Wesnes KA, Scholey AB.(PubMed)
(16) Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm) by Kennedy DO, Little W, Scholey AB(PubMed)
(17) Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm) by Kennedy DO, Scholey AB, Tildesley NT, Perry EK, Wesnes KA.(PubMed)
(18) Carnosic acid suppresses the production of amyloid-β 1-42 and 1-43 by inducing an α-secretase TACE/ADAM17 in U373MG human astrocytoma cells by Yoshida H¹, Meng P², Matsumiya T², Tanji K³, Hayakari R², Xing F², Wang L², Tsuruga K⁴, Tanaka H⁵, Mimura J⁶, Kosaka K⁷, Itoh K⁶, Takahashi I⁸, Imaizumi T(PubMed)².
(19) Molecular Interaction of Acetylcholinesterase with Carnosic Acid Derivatives: A Neuroinformatics Study by Merad M, Soufi W, Ghalem S, Boukli F, Baig MH, Ahmad K, Kamal MA.(PubMed)
(20) Effect of aromatherapy on patients with Alzheimer's disease by Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K(PubMed)
(21) Uncaria rhynchophylla ameliorates cognitive deficits induced by D-galactose in mice.

Xian YF, Lin ZX, Zhao M, Mao QQ, Ip SP, Che CT(PubMed)

(22) Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins by Fujiwara H, Iwasaki K, Furukawa K, Seki T, He M, Maruyama M, Tomita N, Kudo Y, Higuchi M, Saido TC, Maeda S, Takashima A, Hara M, Ohizumi Y, Arai H(PubMed)
(23) Novel cognitive improving and neuroprotective activities of Polygala tenuifolia Willdenow extract, BT-11 by Park CH, Choi SH, Koo JW, Seo JH, Kim HS, Jeong SJ, Suh YH.(PubMed)

(24) Tenuifolin, an extract derived from tenuigenin, inhibits amyloid-beta secretion in vitro by Lv J, Jia H, Jiang Y, Ruan Y, Liu Z, Yue W, Beyreuther K, Tu P, Zhang D(PubMed)
(25) Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid beta-protein in cultured cells by Jia H, Jiang Y, Ruan Y, Zhang Y, Ma X, Zhang J, Beyreuther K, Tu P, Zhang D(PubMed)
(26) Induction of NGF synthesis in astrocytes by onjisaponins of Polygala tenuifolia, constituents of kampo (Japanese herbal) medicine, Ninjin-yoei-to by Yabe T, Tuchida H, Kiyohara H, Takeda T, Yamada H.(PubMed)
(27) The psychopharmacology of European herbs with cognition-enhancing properties by Kennedy DO, Scholey AB(PubMed)
(28) The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-beta peptide-induced neurotoxicity by Iuvone T, De Filippis D, Esposito G, D'Amico A, Izzo AA(PubMed)
(29) Medicinal plants and Alzheimer's disease: from ethnobotany to phytotherapy by Perry EK, Pickering AT, Wang WW, Houghton PJ, Perry NS.(PubMed)
(30) Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders by Howes MJ, Perry NS, Houghton PJ(PubMed)
(31) Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies by Geromichalos GD, Lamari FN, Papandreou MA, Trafalis DT, Margarity M, Papageorgiou A, Sinakos Z.(PubMed)
(32) Ethnobotanical treatment strategies against Alzheimer's disease by Howes MJ, Houghton PJ.(PubMed)
(33) Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trial by Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, Hejazi SSh, Yousefi MH, Alimardani R, Jamshidi A, Zare F, Moradi A.(PubMed)
(34) Effects of active constituents of Crocus sativus L., crocin on streptozocin-induced model of sporadic Alzheimer's disease in male rats by Khalili M, Hamzeh F.(PubMed)
(35) Neuroprotective effects of Bacopa monnieri in experimental model of dementia by Saini N, Singh D, Sandhir R.(PubMed)
(36) Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer's disease model by Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K.(PubMed)
(37) Na⁺-K⁺-ATPase, a potent neuroprotective modulator against Alzheimer disease by Zhang LN, Sun YJ, Pan S, Li JX, Qu YE, Li Y, Wang YL, Gao ZB.(PubMed)
(38) Neurotransmitter metabolic enzymes and antioxidant status on Alzheimer's disease induced mice treated with Alpinia galanga (L.) Willd by Hanish Singh JC, Alagarsamy V, Sathesh Kumar S, Narsimha Reddy Y.(PubMed)
(39) Galangin, a flavonol derived from Rhizoma Alpiniae Officinarum, inhibits acetylcholinesterase activity in vitro by Guo AJ, Xie HQ, Choi RC, Zheng KY, Bi CW, Xu SL, Dong TT, Tsim KW.(PubMed)
(40) Neuroprotective effect of Alpinia galanga (L.) fractions on Aβ(25-35) induced amnesia in mice by Hanish Singh JC, Alagarsamy V, Diwan PV, Sathesh Kumar S, Nisha JC, Narsimha Reddy Y.(PubMed)
(41) Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease by Konrath EL, Passos Cdos S, Klein LC Jr, Henriques AT(PubMed)
(42) Ethnobotanical treatment strategies against Alzheimer's disease.

Howes MJ, Houghton PJ(PubMed)

(43) Alzheimer's disease drugs: an application of the hormetic dose-response model by Calabrese EJ.(PubMed)
(44) Treatment of behavioral and psychological symptoms of Alzheimer-type dementia with Yokukansan in clinical practice by Hayashi Y, Ishida Y, Inoue T, Udagawa M, Takeuchi K, Yoshimuta H, Kiue K, Ninomiya Y, Kawano J, Sameshima T, Kawahara T, Goto I, Shudo K, Kurayama S, Nakamura J, Okahara K, Mitsuyama Y.(PubMed)
(45) Effects of Yokukansan on behavioral and psychological symptoms of dementia in regular treatment for Alzheimer's disease by Okahara K, Ishida Y, Hayashi Y, Inoue T, Tsuruta K, Takeuchi K, Yoshimuta H, Kiue K, Ninomiya Y, Kawano J, Yoshida K, Noda S, Tomita S, Fujimoto M, Hosomi J, Mitsuyama Y.(PubMed)
(46) A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients by Iwasaki K, Satoh-Nakagawa T, Maruyama M, Monma Y, Nemoto M, Tomita N, Tanji H, Fujiwara H, Seki T, Fujii M, Arai H, Sasaki H.(PubMed)
(47) Ameliorative effects of yokukansan on learning and memory deficits in olfactory bulbectomized mice by Yamada M, Hayashida M, Zhao Q, Shibahara N, Tanaka K, Miyata T, Matsumoto K.(PubMed)
(48) [A case of severe hypokalemia caused by a Chinese herbal remedy (Yokukansan) in an 81-year-old woman with dementia].[Article in Japanese]by Nishiyama N, Takeshita M, Tanaka K, Miyao M, Mizuno Y.(PubMed)
(49) The use of herbal medicine in Alzheimer's disease-a systematic review by Dos Santos-Neto LL, de Vilhena Toledo MA, Medeiros-Souza P, de Souza GA.(PubMed)



(50) A randomized, double-blind, placebo-controlled clinical trial of the Chinese herbal medicine "ba wei di huang wan" in the treatment of dementia by Iwasaki K, Kobayashi S, Chimura Y, Taguchi M, Inoue K, Cho S, Akiba T, Arai H, Cyong JC, Sasaki H.(PubMed)
(51) The Use of Herbal Medicine in Alzheimer's Disease—A Systematic Review by Leopoldo Luiz dos Santos-Neto,¹ Maria Alice de Vilhena Toledo,² Patrícia Medeiros-Souza,³ and Gustavo Almeida de Souza(PubMed)³

Alzheimer's disease in Foods Points of View

 Kyle J. Norton(Draft Article)

Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas, named after German physician Alois Alzheimer. Alzheimer's destroys brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal. 
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease. It may be a result of  cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions and psychosocial factors (eg, high education, active social engagement, physical exercise, and mentally stimulating activity)(1) Strong evidences emerged in epidemiological studies suggested that certain foods(2) may have potential in reduced risk and treatments of Alzheimer's disease.

1. Cruciferous vegetables
Cruciferous vegetables are the group of vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc..
Epidemiological studies has demonstrated reduced risk of prostate cancer in cruciferous consumption. The study of 2148 community-based elderly subjects (aged > or = 65 years) without dementia in New York, after 3.9 years,  253 subjects developed AD during a follow-up. Dietary pattern (DP) analysis of food combination indicated that higher intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables and a lower intake of high-fat dairy products, red meat, organ meat, and butter are associated to reduced risk of  AD.(1)

2. Tomatos
Tomato is a red, edible fruit, genus Solanum, belonging to family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose and often in green house.
Lycopene and alpha carotene found in tometos induced symptoms of AD through inhibition of amyloid beta (Aβ) formation, deposition and fibril formation either by reducing the levels of p35 or inhibiting corresponding enzymes(2). In the study of Antioxidants, such as tocopherols and carotenoids, have been implicated in the prevention of degenerative diseases showed that aging population exhibit a age related decline of levels retinol, total tocopherols, total xanthophylls and total carotenoids(3).

3. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties.
 S-allyl-L-cysteine (SAC), an active chemical constituents of garlic, showed to inhibit several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated with AD. through up and down regulations(4) with intervention to prevent free radicals causes of deterioration of cognitive functions and neurobehavioral activities(5). The Central Food Technological Research Institutesupported the binding ability of SAC to Abeta and inducing a partially folded conformation in Abeta.(6) and suggested that consumption of garlic may reduced risk of AD, due to inhibition of Abeta aggregation in human brain(7).

4. Ginger
Ginger (Zingiber officinale) or ginger root is the genus Zingiber, belonging to the family Zingiberaceae, native to Tamil. It has been used in traditional and Chinese medicine to treat dyspepsia, gastroparesis, constipation, edema, difficult urination, colic, etc.
In the Alzheimer disease (AD) rat model, ginger root extract (GRE) was administered intra-gastrically to rats after 35 days, exhibited the protective effect against AD through reversed behavioral dysfunction and prevented AD-like symptoms(8).  [6]-gingerol, a pungent ingredient of ginger, pretreatment protected against Aβ(25-35)-induced cytotoxicity and apoptotic cell death such as DNA fragmentation, disruption of mitochondrial membrane potential, elevated Bax/Bcl-2 ratio, and activation of caspase-3 via augmentation of antioxidant capacity(9) and inhibition of acetylcholinesterase activities and prevention of lipid peroxidation in the brain(10).

5. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in traditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc. 
Evidences of epidemiological studies suggestion of curcumin in reduced risk of Ad progression. Suggestion of curcumin in treating Alzheimer's disease (AD) depend on the ability to penetrate the blood-brain barrier(11) and showed to inhibit progression of deposit of  beta-amyloid aggregation.(12).
A novel polymeric nanoparticle (PEG-PLGA) encapsulated curcumin, induce adult neurogenesis through activation of the canonical Wnt/β-catenin pathway(secreted signalling proteins  released by one cell population will trigger concentration-dependent responses in other cells located some distance away)(13) triggering brain self-repair mechanis(14).  Unfortunately, a 24-week randomized, double blind, placebo-controlled study conducted by the David Geffen School of Medicine at UCLA, oral administration showed no biochemical evidence of efficacy of Curcumin C3 Complex® in AD(15).

6. Cinnamon
Cinnamon is a spice derived from the inner bark of tree, native to South East Asia, of over 300 species of the genus Cinnamomum, belonging to the family Lauraceae.. The herb has been use in herbal and traditional medicine as anti-fungal and bacteria level to improve reproductive organ, prevent flatulence and intestinal cramping, treat indigestion, diarrhea, bad breath, headache, migraine, etc.
Aqueous extract of cinnamon showed to inhibit tau aggregation in vitro and can even induce dissociation of tangles isolated from AD brain and cinnamaldehyde (CA), the organic compound of cinnamon
protected tau from oxidation caused by the reactive oxygen species, H2O2, and prevented subsequent formation of high molecular weight species that are considered to stimulate tangle formation(16) and inhibited tau aggregation associated with Alzheimer's disease in vitro(17). Other study insisted that cinnamon extract (CEppt), markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells and oral administration in AD patients, showed to reduce longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in the brain(18).

7. Black pepper
Black pepper is a  is a flowering vine in the genus Pipper, belonging to the family Piperaceae. It has been used in folk medicine in treating constipation, diarrhea, earache, gangrene, heart disease, hernia, hoarseness, indigestion, insect bites, insomnia, joint pain, etc.
Piperine, a main active alkaloid in black pepper exhibited significantly improved memory impairment and neurodegeneration in hippocampus associated with the decrease lipid peroxidation and acetylcholinesterase enzyme(19). In the evaluation the Piperine therapeutic effects in Alzheimer's Disease. at 2 mg/kg dose, reduced the SOD values, increased the acetylcholenesterase values, and reduced immobility and has shown superior results than Donepezil (5 mg/kg), AD drug(20).

8. Green Tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Green tea polyphenols (GTPs) may be a next potential agent in protection of neurodegenerative diseases such as Alzheimer's disease (AD). GTPs have found to inhibit amyloid fibril formation and protect neurons from toxicity induced by β-amyloid and OA-induced neurotoxicity by enhancing the amelioration of learning and memory impairments and also reduction of tau hyperphosphorylation(21). Epigallocatechin gallate polyphenols, isolated from green tea, in a a selective inhibitor of PKC., combination of EGCG and resveratrol protected against GF 109203X-induced cell death and cytoskeleton degeneration, with a maximal effect at 1 and 3 μM, respectively and cells treated increased PKC gamma (γ) activation and promoted neuronal interconnections(22). (-)-epigallocatechin-3 gallate (EGCG) alone also showed to reduce amyloid-β (Aβ) production in both neuronal and mouse Alzheimer's disease (AD) models(23).

9. Coffee
Coffee made from the roasted seeds of the genus Coffee, belonging to the family Rubiaceae native to southern Arabia. Coffee may consist certain substances, effecting the risk of Alzheimers' disease. AD mice given caffeine in their drinking water from young adulthood into older age showed to inhibit memory and cgnitive impairment and lower brain levels of amyloid-beta; Abeta)(24)(25). In mice with Alzheimers' disease caused by dysregulated endoplasmic reticulum (ER) calcium (Ca ²⁺), induced deletion of RyanR3, showed the enhancement of coffee in activation of RyanRs which protects AD neurons from synaptic and network dysfunction(26). Intake of 5 cups of coffee per day(moderate caffeine intake) found to protect against the development of certain cognitive impairment and decreased hippocampal amyloid-beta (Abeta) levels through suppression of both beta-secretase (BACE1), a beta-site amyloid precursor protein cleaving enzyme 1 and presenilin 1 (PS1)/gamma-secretase expression(mutations in the presenilin proteins)(27) and  protect against or treat AD in a mouse model(28)

10. Red wine
Red wine made from made  dark-coloured (black) grape varieties as a result of anthocyan pigments  present in the skin of the grape.
Red wine may be a therapeutic potential  for treating AD patinets through reduction of forming of beta-amyloid peptid. In human umbilical vein endothelial cells (HUVECs), black grape skin extract rinhibited the ROS production, protects the cellular membrane from oxidative damage, and consequently prevents DNA fragmentation(29).  Red wine extract resveratrol, inother study inhibited the expression of soluble oligomers of of the amyloid-β (Aβ) peptide cause neurotoxicity, synaptic dysfunction, and memory impairments(30). Polyphenols derived from red wine, according to Mount Sinai School of Medicine, New York, may protect against cognitive deterioration of Alzheimer's disease, thriugh generation and assembly of β-amyloid peptides into neurotoxic oligomeric aggregated species(31).

10. Olive oil
Olive is belongs to the the family Oleaceae, native to the coastal areas of the eastern Mediterranean Basin and south end of the Caspian Sea. Its fruit, is also called the olive and the source of olive oil.
Oleuropein aglycone, the main polyphenol derived from extra virgin olive oil, in the study of the double transgenic TgCRND8 mice, showed to improve the cognitive performance and reduce ß-amyloid levels and plaque deposits, through  increase of autophagic markers expression and of lysosomal (break down waste materials and cellular debris)activity(32), induction of the Aβ transgene expression(33) and enhancement of Aβ clearance from the brain(34). the study by VA Medical Center, aslo dound that EVOO inhibited learning and memory deficits found in aging and diseases, due to overproduction of amyloid-β protein, and reversed oxidative damage in the brain(35).

11. Fish oil
Fish oil derived from the tissues of oily fish, contains high amount of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), etc.
Epidemiological studies suggested that higher dietary intake of ω-3 PUFA reduced risk of incident AD and slower cognitive decline(36) through reduction of plasma levels of Aβ42(37) and may induce the PTEN expression(ova tumor suppressor gene) by activation of peroxisome proliferator-activated receptor(regulating the expression of genes)(38). genetically, defection of the ε4 allele of the APOE gene (APOE4), the Central Michigan University, in the mu-p75 saporin (SAP)-induced mouse model of AD, daily treatments of Cerise(®) Total-Body-Rhythm™ (TBR; containing tart cherry extract, Nordic fish oil, and refined emu oil), reduced the severity of cognitive deficits in disorders involving cholinergic deficits(39). 

Taking altogether, without going into reviews, The list of foods above may be effective in reduced risk and treatment of Alzheimers' disease through improvment of cognitive function in reduced plasma levels of Aβ42 and ß-amyloid levels and plaque deposits. Some researchers suggested that larger sample and multi centers studies are necessary to indentify the principle ingredients and validate their effectiveness. As always, all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying

References
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(2) Carotenoids and Alzheimer's disease: an insight into therapeutic role of retinoids in animal models by Obulesu M¹, Dowlathabad MR, Bramhachari PV.(PubMed)
(3) Carotenoid, tocopherol, and retinol concentrations in elderly human brain by Craft NE¹, Haitema TB, Garnett KM, Fitch KA, Dorey CK.(PubMed)
(4) The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD) by Ray B¹, Chauhan NB, Lahiri DK.(PubMed)
(5) S-allyl cysteine attenuates oxidative stress associated cognitive impairment and neurodegeneration in mouse model of streptozotocin-induced experimental dementia of Alzheimer's type by Javed H¹, Khan MM, Khan A, Vaibhav K, Ahmad A, Khuwaja G, Ahmed ME, Raza SS, Ashafaq M, Tabassum R, Siddiqui MS, El-Agnaf OM, Safhi MM, Islam F.(PubMed)
(6) Anti-amyloidogenic activity of S-allyl-L-cysteine and its activity to destabilize Alzheimer's beta-amyloid fibrils in vitro by Gupta VB¹, Rao KS.(PubMed)
(7) Garlic extract exhibits antiamyloidogenic activity on amyloid-beta fibrillogenesis: relevance to Alzheimer's disease by Gupta VB¹, Indi SS, Rao KS(PubMed)
(8) Protective effects of ginger root extract on Alzheimer disease-induced behavioral dysfunction in rats by Zeng GF¹, Zhang ZY, Lu L, Xiao DQ, Zong SH, He JM.(PubMed)
(9) [6]-Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system by Lee C¹, Park GH, Kim CY, Jang JH.(PubMed)
(10) Inhibition of acetylcholinesterase activities and some pro-oxidant induced lipid peroxidation in rat brain by two varieties of ginger (Zingiber officinale) by Oboh G¹, Ademiluyi AO, Akinyemi AJ.(PubMed)
(11) Highly stabilized curcumin nanoparticles tested in an in vitro blood-brain barrier model and in Alzheimer's disease Tg2576 mice by Cheng KK¹, Yeung CF, Ho SW, Chow SF, Chow AH, Baum L.(PubMed)
(12) Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study by Ringman JM¹, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL, Cole GM.(PubMed)
(13) Curcumin-Loaded Nanoparticles Potently Induce Adult Neurogenesis and Reverse Cognitive Deficits in Alzheimer's Disease Model via Canonical Wnt/β-Catenin Pathway by Tiwari SK¹, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, Karmakar M, Kumari M, Chauhan LK, Patel DK, Srivastava V, Singh D, Gupta SK, Tripathi A, Chaturvedi RK, Gupta KC.(PubMed)
(14) Curcumin-Loaded Nanoparticles Potently Induce Adult Neurogenesis and Reverse Cognitive Deficits in Alzheimer's Disease Model via Canonical Wnt/β-Catenin Pathway by Tiwari SK¹, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, Karmakar M, Kumari M, Chauhan LK, Patel DK, Srivastava V, Singh D, Gupta SK, Tripathi A, Chaturvedi RK, Gupta KC.(PubMed)
(15) Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study by Ringman JM¹, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL, Cole GM.(PubMed)
(16) Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis by George RC¹, Lew J, Graves DJ.(PubMed)
(17) Cinnamon extract inhibits tau aggregation associated with Alzheimer's disease in vitro by Peterson DW¹, George RC, Scaramozzino F, LaPointe NE, Anderson RA, Graves DJ, Lew J.(PubMed)
(18) Orally administrated cinnamon extract reduces β-amyloid oligomerization and corrects cognitive impairment in Alzheimer's disease animal models by Frydman-Marom A¹, Levin A, Farfara D, Benromano T, Scherzer-Attali R, Peled S, Vassar R, Segal D, Gazit E, Frenkel D, Ovadia M(PubMed)
(19) Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease. by Chonpathompikunlert P¹, Wattanathorn J, Muchimapura S.(PubMed)
(20) Preparation, characterization, in vivo and biochemical evaluation of brain targeted Piperine solid lipid nanoparticles in an experimentally induced Alzheimer's disease model by Yusuf M¹, Khan M, Khan RA, Ahmed B.(PubMed)
(21) Green tea polyphenols protect against okadaic acid-induced acute learning and memory impairments in rats by Li H¹, Wu X¹, Wu Q¹, Gong D¹, Shi M¹, Guan L¹, Zhang J¹, Liu J¹, Yuan B¹, Han G², Zou Y³(PubMed)
(22) Neuroprotective effects of resveratrol and epigallocatechin gallate polyphenols are mediated by the activation of protein kinase C gamma. Menard C¹, Bastianetto S², Quirion R³(PubMed)
(23) Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation by Zhang SQ¹, Sawmiller D, Li S, Rezai-Zadeh K, Hou H, Zhou S, Shytle D, Giunta B, Fernandez F, Mori T, Tan J.(PubMed)
(24) Caffeine and coffee as therapeutics against Alzheimer's disease by Arendash GW¹, Cao C.(PubMed)
(25) Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice by Arendash GW¹, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J, Citron BA, Lin X, Echeverria V, Potter H.(PubMed)
(26) The role of ryanodine receptor type 3 in a mouse model of Alzheimer disease by Liu J¹, Supnet C², Sun S¹, Zhang H¹, Good L³, Popugaeva E⁴, Bezprozvanny I⁵.(PubMed)
(27) Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice by Arendash GW¹, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J, Citron BA, Lin X, Echeverria V, Potter H.(PubMed)
(28) Caffeine and coffee as therapeutics against Alzheimer's disease by Arendash GW¹, Cao C.
(PubMed)
(29) Red wine micronutrients as protective agents in Alzheimer-like induced insult by Russo A¹, Palumbo M, Aliano C, Lempereur L, Scoto G, Renis M.(PubMed)
(30) rion protein-mediated toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1 by Rushworth JV¹, Griffiths HH, Watt NT, Hooper NM(PubMed)
(31) Novel role of red wine-derived polyphenols in the prevention of Alzheimer's disease dementia and brain pathology: experimental approaches and clinical implications by Pasinetti GM.(PubMed)
(32) The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology by Grossi C¹, Rigacci S, Ambrosini S, Dami TE, Luccarini I, Traini C, Failli P, Berti A, Casamenti F, Stefani M(PubMed)
(33) Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit by Diomede L¹, Rigacci S, Romeo M, Stefani M, Salmona M(PubMed)
(34) Olive-oil-derived oleocanthal enhances β-amyloid clearance as a potential neuroprotective mechanism against Alzheimer's disease: in vitro and in vivo studies by Abuznait AH¹, Qosa H, Busnena BA, El Sayed KA, Kaddoumi A(PubMed).
(35) Extra virgin olive oil improves learning and memory in SAMP8 mice by Farr SA¹, Price TO, Dominguez LJ, Motisi A, Saiano F, Niehoff ML, Morley JE, Banks WA, Ercal N, Barbagallo M.(PubMed)
(36) Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease by Dacks PA¹, Shineman DW, Fillit HM.(PubMed)
(37) Nutrient intake and plasma β-amyloid by Gu Y¹, Schupf N, Cosentino SA, Luchsinger JA, Scarmeas N.(PubMed)
(38) Diets involved in PPAR and PI3K/AKT/PTEN pathway may contribute to neuroprotection in a traumatic brain injury by Kitagishi Y¹, Matsuda S.(PubMed)
(39) Combinatorial treatment of tart cherry extract and essential fatty acids reduces cognitive impairments and inflammation in the mu-p75 saporin-induced mouse model of Alzheimer's disease.

Matchynski JJ¹, Lowrance SA, Pappas C, Rossignol J, Puckett N, Sandstrom M, Dunbar GL.(PubMed)

Vitamin B12 and Endometrial Cancer

Kyle J. Norton

The incidence of endometrial cancer among white women are higher in comparison of black. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.
Vitamin B12, also known as cobalamin, is a water-soluble vitamin, found abundantly in a variety of foods, such as fish, shellfish, meat, eggs, dairy products, etc. and plays an important role in regulating the functions of nervous system and formation of blood.

Epidemiological studies, focusing vitamin B12 in reduced risk of endometrial cancer have produced inconsistent results, but in certain studies, vitamin B12 composted with other micro nutrients was found to be effective. Neurotoxicity caused by Paclitaxel/carboplatin chemotherapy for cancer (TC therapy) may induce peripheral neuropathy, the study of Goshajinkigan (a traditional Japanese herbal medicine) composed with vitamin B12, showed to inhibit the progression of peripheral neuropathy, thus alleviating the symptoms of endometrial cancer(1). One-carbon metabolism, vitamin B12 showed no influence endometrial cancer risk but for women with with the MTHFR 677 TT or MTHFR 1298 CC genotype, the dietary factors including vitamin B12 are associated to the protective effect against endometrial cancer(2). Due to the influence of Folate, methionine, vitamin B(6) and vitamin B(12)  in the one-carbon metabolism pathway which is critical for DNA synthesis, methylation and repair some researchers suggested that intake of these nutrients may be associated with an reduced risk of breast, colon and endometrial cancers(3).

Taking altogether. without going into reviews, vitamin B12 composed with other micronutrients may be efective in reduced risk and treatment of endometrial cancer but large example size are necessary to validate their claims. Over doses of the vitamin may induce symptoms of toxicity, including headache, giddiness and abnormal heart functioning, etc., please make sure to follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Objective evaluation of the alleviating effects of Goshajinkigan on peripheral neuropathy induced by paclitaxel/carboplatin therapy: A multicenter collaborative study by Kaku H¹, Kumagai S, Onoue H, Takada A, Shoji T, Miura F, Yoshizaki A, Sato S, Kigawa J, Arai T, Tsunoda S, Tominaga E, Aoki D, Sugiyama T.(PubMed)
(2) One-carbon metabolism factors and endometrial cancer risk by Liu JJ¹, Hazra A, Giovannucci E, Hankinson SE, Rosner B, De Vivo I.(PubMed)
(3) Folate, vitamin B(6) , vitamin B(12) , methionine and alcohol intake in relation to ovarian cancer risk by Harris HR¹, Cramer DW, Vitonis AF, DePari M, Terry KL.(PubMed)