Natural Supplements to Ward Off Alzheimer’s (Aging on the Brain: The Neurodegenerative Battle)

Coenzyme Q10 (CoQ10) also has powerful antioxidant properties. A Chinese study treated aged transgenic mice over-expressing Alzheimer presenilin 1-L235P (leucine-to-proline mutation at codon 235, 16 to 17 months old) by feeding them CoQ10 for 60 days (1,200 mg/kg(-1)/d (-1)).²² The treatment partially attenuated A beta overproduction and intracellular A beta deposit in the cortex of the transgenic mice compared with the age-matched untreated transgenic mice. An increased oxidative stress and decreased activity of superoxide dismutase (SOD) occurred in the transgenic mice relative to the wild-type mice, and supplementation of CoQ10 partially decreased malondialdehyde level and upregulated the activity of SOD. A Japanese in vitro study found CoQ10 dose-dependently inhibited beta-amyloid fibrils formation from A beta, as well as their extension, and destabilized preformed beta-amyloid fibrils.²³ The anti-amyloidogenic effects of CoQ10 were slightly weaker than nordihydroguaiaretic acid and myricetin.

Green tea is a well-known antioxidant with high levels of polyphenols. A Chinese study injected D-galactose (120 mg/kg) and A beta25-35 into mice for 12 weeks to establish Alzheimer-like mice.²⁴ Green tea polyphenols ameliorated the deleterious effects of D-galactose and A beta25-35 improving the animals’ learning, memory, prolonged latency time and autonomic activities while significantly reducing the error numbers. Similarly, researchers from a Japanese animal model found that long-term administration of green tea catechins provided effective prophylactic benefits against A beta-induced cognitive impairment by increasing antioxidative defenses.²⁵

In a 2007 model, researchers stated that accumulation of iron where neurons degenerate in Alzheimer's disease may play a role in the oxidative stress-induced process of neurodegeneration.²⁶ Iron chelators like VK-28 and its multi-functional derivative, M-30, as well as (-)-epigallocatechin-3-gallate (EGCG), the main polyphenol constituent of green tea, can offer potential benefits for Alzheimer's disease. In the serum deprivation model, M-30 and EGCG decreased apoptosis of cells through multiple protection methods, and promoted morphological changes, resulting in axonal growth-associated protein-43 (GAP-43) implicating neuronal differentiation. Both M-30 and EGCG significantly reduced the levels of cellular holo-APP in cells. EGCG reduced the levels of toxic A beta peptides in CHO cells over-expressing the APP “Swedish” mutation.

Resveratrol is found in the skin of red grapes, blueberries, peanuts and other plants. Researchers from a study at Howard Hughes Medical Institute, Boston, reported in cell-based models for Alzheimer’s and amyotrophic lateral sclerosis (ALS), SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival.²⁷ In the inducible p25 transgenic mouse, a model of Alzheimer’s and tauopathies, resveratrol reduced neurodegeneration in the hippocampus; prevented learning impairment; and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. In addition, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration.

In another study out of New York, Tg2576 mice, which model Alzheimer’s disease-type A beta-protein neuropathology, received either Cabernet Sauvignon with 6 percent ethanol and 0.2 mg/L of resveratrol, a comparative amount of ethanol or water alone.²⁸ Researchers found the Cabernet Sauvignon significantly attenuated Alzheimer's disease-type deterioration of spatial memory function and A beta neuropathology relative to control Tg2576 mice.

A Chinese study randomly divided 84 Kunming female mice into six groups.²⁹ After 60 days, researchers concluded resveratrol of every dosage could improve the performance records of behavior tests in Alzheimer mice, inhibit the SOD vitality and malondialdehyde (MDA) level both in the serum and in the brain, and could suppress the acetylcholinesterase vitality and the bax expression without a side effects of endometrial hyperplasia.

High blood concentrations of folic acid, a form of the water-soluble vitamin B9, are associated with positive cognitive function. In a 2008 six-month, randomized, double blind, placebo-controlled study, 57 outpatients with probable Alzheimer's disease were treated concurrently with cholinesterase inhibitors (ChI) and either folic acid or a placebo.³⁰ At the end of the six months, there were no significant baseline differences or use of individual ChI between the two arms. A significant difference was seen in the change from baseline in combined IDAL and Social Behaviour scores between arms versus the placebo, but there was no change in MMSE scores. Sixteen of 23 subjects receiving folic acid and seven out of 18 placebo subjects were classified as National Institute of Clinical Excellence (NICE) responders (P=0.05). Researchers concluded that response to ChI in patients with Alzheimer’s may be improved by the use of folic acid.

A study published in The Lancet randomly assigned 818 participants 800 μg/d folic acid or placebo for three years.³¹ Serum folate concentrations increased by 576 percent and plasma total homocysteine concentrations decreased by 26 percent in participants taking folic acid compared with those taking placebo. The three-year change in memory, information processing speed and sensorimotor speed were significantly better in the folic acid group than in the placebo group.

In an Italian study published in the Journal of the American College of Nutrition, 471 consenting subjects participating in the Monzino 80-plus study, a door-to-door population-based survey among very old subjects living in Northern Italy, were assessed for their serum vitamin B12 and folate concentrations.³² Cognitive and functional evaluations included MMSE, IADL and Spontaneous Behavior Interview-basic Activities of Daily Living (SBI-bADL). The MMSE, IADL and SBI-bADL scores were all significantly correlated with folate concentrations, while no significant associations were found with vitamin B12 concentrations. Folate showed a highly significant, curvilinear association with both cognitive and functional scores (P<0.0001). Subjects in low and middle folate tertiles had significantly higher odds ratios for dementia. The findings suggested subclinical folate deficiency may represent a risk factor for the cognitive decline associated with aging that could contribute to Alzheimer’s as well as other dementia development.

Other B vitamins have been studied for their effects on Alzheimer’s disease. A Swedish study used a population-based sample to examine the associations of vitamin B12 and folate with cognitive functioning in clinical (n=44) and preclinical (n=39) Alzheimer’s.³³ The groups were subdivided in terms of low versus normal levels of B12, and low versus normal folate levels. The preclinical Alzheimer’s group performed better than the Alzheimer’s group across most cognitive tests. The effects of low vitamin B12 and folate levels were negligible across all cognitive tests in clinical and preclinical Alzheimer’s indicating the influence of vitamin B deficiency on cognitive functioning is overshadowed by the neurodegenerative processes associated with Alzheimer's disease.

Another trial was conducted at En Chu Kong Hospital, Taipei, Taiwan where 89 male and female patients aged more than 50-years-old with mild to moderate Alzheimer’s, normal folic acid and vitamin B12 concentrations were randomized to receive 500 mg of vitamin B12; plus a multivitamin supplement containing 5 mg of pyridoxine (B6), 1 mg of folic acid, iron and other vitamins; or placebos for 26 weeks.³⁴ At week 26, there were no significant differences in cognition or ADL function scores between the two groups; the mean between-group difference in serum homocysteine concentration versus placebo was -2.²⁵ (P = 0.008) and the mean serum concentrations of vitamin B12 and folic acid were significantly higher, but within normal range, in the multivitamin group compared with placebo. The study showed a multivitamin supplement containing vitamins B6, B12 and folic acid for 26 weeks decreased homocysteine concentrations, but no statistically significant beneficial effects on cognition or ADL function were found between multivitamin and placebo.

Citicoline, a form of the B vitamin choline that supports phospholipid production in the brain, has been used to treat neurodegenerative disorders. In a double blind, placebo-controlled, randomized clinical trial, 30 patients with mild to moderate senile dementia of the Alzheimer type were treated with 1,000 mg/d of citicoline (as Cognizin™, from Kyowa Hakko) (n=13) or placebo (n=17) for 12 weeks.³⁵ Compared to placebo, citicoline improved cognitive performance in Alzheimer's disease patients with apolipoprotein E (APOE); this improvement was more pronounced in patients with mild dementia. Citicoline also increased cerebral blood flow velocities in comparison with the placebo (P<0.05) when transcranial Doppler recordings from both hemispheres were considered together, as well as diastolic velocity in the left middle cerebral artery (P<0.05). Patients treated with citicoline showed an increase in the percentage of brain bioelectrical activity of alpha (occipital electrodes) and theta type (left side electrodes), accompanied by a decrease in relative delta activity particularly marked in the left temporal lobe. Significant differences with respect to placebo (P<0.05) were observed for theta activity in several fronto-parieto-temporal electrodes of the left hemisphere. Treatment with citicoline tended to reduce serum IL-1 beta levels, mainly after four weeks of administration, with no modified blood histamine content. In addition, neither adverse side effects nor alterations in biological and hematological parameters were induced by citicoline.

An Italian study investigated the effects of citicoline (as posatirelin) and ascorbic acid (inactive drug) in elderly patients suffering from late-onset Alzheimer's disease for three months.³⁶ The once daily treatment lasted for three months and was followed by one-month oral treatment with a placebo. At the end of the treatment, Gottfries-Bråne-Steen (GBS) subscale and factor scores assessing intellectual and emotional impairments, orientation and memory, ability to perform activities of daily living, depression-anxiety, attention and motivation were improved in the postatirelin group, showing significant differences with respect to the citicoline and/or ascorbic acid groups.

In a Spanish study, elderly subjects with memory deficits and without dementia were administered 1,000 mg/d or 500 mg/d of citicoline alone (as Cognizin) or 300 mg/d of citicoline plus 90 mg/d of nimpdipine for four weeks.³⁷ Citicoline, in comparison with the placebo, improved memory in free recall tests, but not in recognition tests. There was a significant improvement in word recall (P<0.005), immediate object recall (P<0.05) and delayed object recall after citicoline treatment (P<0.005). In addition, three subgroups of treatment also showed citicoline’s memory-enhancing activity at doses of 300 to 1,000 mg/d.

Ginkgo biloba is a botanical used to enhance memory. In a 24-week, double blind, placebo-controlled study in Italy, patients 50 to 80 years old suffering from mild to moderate dementia were randomized into one of three treatments: 160 mg/d of Ginkgo biloba (as Flavogin®, from Baif International Products); 5 mg/d of donepezil, a cholinesterase inhibitor; or placebo.³⁸ The results confirmed the clinical efficacy of ginkgo biloba E.S. in Alzheimer's disease compared with donepezil clinical efficacy. There was no evidence of relevant differences in the efficacy of Ginkgo biloba EGb 761 and donepezil in the treatment of mild to moderate Alzheimer’s, justifying the use of both substances. Researchers stated the study helped establish the efficacy and tolerability of Ginkgo biloba E.S. in Alzheimer’s with special respect to moderately severe stages.

A double blind, placebo-controlled trial at UCLA took 10 right-handed persons with age-associated memory impairment (AAMI), aged 47 to 75 years old, and randomly assigned them to either 120 mg of Ginkgo biloba EGb 761 twice daily or a placebo for six months.³⁹ The ginkgo group significantly improved immediate verbal recall compared to the placebo group (P=0.03). The placebo and ginkgo groups did not differ significantly in change in cerebral metabolism. All the subjects showed improvement in immediate recall, which significantly correlated with increased glucose metabolism in the right lateral temporal cortex. Researchers stated Ginkgo biloba appeared to improve verbal memory relative to placebo, and the magnitude of cognitive improvement correlated significantly with resting lateral temporal metabolism.

Despite the sad truth that there is no cure for Alzheimer’s, natural supplements can help slow down the degenerative process and improve brain functions, prolonging the process the disease takes as well as play a role in prevention.

Editor's Note: Looking for more information on nutritional ingredients for cognitive health? INSIDER's Free Webinar, "Cognition and Memory: Consumer Attitudes and Ingredients to Remember", will be available on demand May 22, 2008. Click here to learn more.

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