Vitamins & minerals
A two-year study which involved metabolic testing of 50 people, suggests that Alzheimer's disease consists of three distinct subtypes, each one of which may need to be treated differently. The finding may help explain why it has been so hard to find effective treatments for the disease.
The subtypes are:
The cortical subtype appears to be fundamentally a different condition than the other two.
I note a study I reported on last year, that found different molecular structures of amyloid-beta fibrils in the brains of Alzheimer's patients with different clinical histories and degrees of brain damage. That was a very small study, indicative only. However, I do wonder if there's any connection between these two findings. At the least, I think this approach a promising one.
The idea that there are different types of Alzheimer's disease is of course consistent with the research showing a variety of genetic risk factors, and an earlier study indicating at least two pathways to Alzheimer's.
It's also worth noting that the present study built on an earlier study, which showed that a program of lifestyle, exercise and diet changes designed to improve the body's metabolism reversed cognitive decline within 3-6 months in nine out of 10 patients with early Alzheimer's disease or its precursors. Note that this was a very small pilot program, and needs a proper clinical trial. Nevertheless, it is certainly very interesting.
Bredesen, D.E. 2015. Metabolic profiling distinguishes three subtypes of Alzheimer's disease. AGING, 7 (8), 595-600. Full text at http://www.impactaging.com/papers/v7/n8/full/100801.html
Bredesen, D.E. 2014. Reversal of cognitive decline: A novel therapeutic program. AGING, Vol 6, No 9 , pp 707-717. Full text at http://www.impactaging.com/papers/v6/n9/full/100690.html
Consistent with earlier indications that moderate caffeine consumption may protect against memory decline, a study of genetically engineered mice has found that when the old mice began to show memory impairment, those given caffeine for 2 months performed as well as normal aged mice on cognitive tests, while those given plain drinking water continued to do poorly. The Alzheimer's mice received the equivalent of five 8-oz. cups of regular coffee a day (or two cups of Starbucks coffee, or 14 cups of tea). Moreover, the brains of the caffeinated mice showed nearly a 50% reduction in levels of beta amyloid. The effect appears to be through suppression of both β-secretase and presenilin 1 /g-secretase expression. Caffeine had this effect only on those with Alzheimer’s; normal mice given caffeine through adulthood showed no cognitive benefit.
Arendash, G.W. et al. 2009. Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice. Journal of Alzheimer's Disease, 17 (3), 661-680.
Cao, C. et al. 2009. Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice. Journal of Alzheimer's Disease, 17 (3), 681-697.
High doses of nicotinamide, a form of vitamin B3, has been found to dramatically lower levels of tau protein in mice with Alzheimer's disease. The vitamin also increased proteins that strengthen microtubules, the scaffolding within brain cells along which information travels. Not only did the vitamin prevent memory loss in Alzheimer’s mice, it also slightly improved cognitive performance in normal mice. Nicotinamide is a water-soluble vitamin sold in health food stores. It generally is safe but can be toxic in very high doses. Clinical trials have shown it benefits people with diabetes complications and has anti-inflammatory properties that may help people with skin conditions. Clinical trials with Alzheimer’s patients are now underway.
Green, K.N. et al. 2008. Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau. Journal of Neuroscience, 28, 11500-11510.
A study of 847 Alzheimer's patients has found that those who took 1,000 international units of vitamin E twice a day, were 26% less likely to die over a five-year period than people who didn't take vitamin E. It also appears that taking vitamin E plus a cholinesterase inhibitor may be more beneficial than taking either agent alone.
The research was presented at the American Academy of Neurology Annual Meeting in Chicago, April 12 – April 19.
Several studies have shown that eating fish, which is high in omega-3 fatty acids, may protect against Alzheimer's disease. A Swedish study has now tested whether supplements could have similar effects. Patients with mild-to-moderate Alzheimer’s who took 1.7 grams of DHA and .6g of EPA showed the same rate of cognitive decline as those taking a placebo, however, among a subgroup of 32 patients with very mild cognitive impairment, those who took the fatty acids experienced less decline in six months compared with those who took placebo. It may be that anti-inflammatory effects are an important reason for the benefit, potentially explaining why effects were seen only in those with very early-stage disease, when levels of inflammation seem to be higher.
Freund-Levi;, Y. et al. 2006. w-3 Fatty Acid Treatment in 174 Patients With Mild to Moderate Alzheimer Disease: OmegAD Study: A Randomized Double-blind Trial. Archives of Neurology, 63, 1402-1408.
A "cocktail" of dietary supplements (omega-3 fatty acids, uridine and choline) has been found to dramatically increase the amount of membranes that form brain cell synapses in gerbils. The treatment is now in human clinical trials. It is hoped that such treatment may significantly delay Alzheimer's disease. The treatment offers a different approach from the traditional tactic of targeting amyloid plaques and tangles. Choline can be found in meats, nuts and eggs, and omega-3 fatty acids are found in a variety of sources, including fish, eggs, flaxseed and meat from grass-fed animals. Uridine, which is found in RNA and produced by the liver and kidney, is not obtained from the diet, although it is found in human breast milk.
Wurtman, R.J., Ulus, I.H., Cansev, M., Watkins, C.J., Wang L. & Marzloff, G. 2006. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Research, Available online ahead of print 21 April 2006.
In cell studies, resveratrol has been found to lower levels of amyloid-beta peptides. Resveratrol is a natural compound occurring in abundance in grapes, berries and peanuts. The highest concentration has been reported in wines prepared from Pinot Noir grapes. The anti-amyloidogenic effect of resveratrol observed in cell cultures does not however necessarily mean that the beneficial effect can result simply from eating grapes or drinking wine. Further research aims to develop more active and more stable compounds.
Marambaud, P., Zhao, H. & Davies, P. 2005. Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid- Peptides. Journal of Biological Chemistry, 280, 37377-37382.
In a study of people with mild cognitive impairment, those who took the drug donepezil were at reduced risk of progressing to a diagnosis of Alzheimer's during the first years of the trial, but by the end of the 3-year study there was no benefit from the drug. Of the 769 participants, 212 developed possible or probable Alzheimer’s within the 3-year study period; the donepezil group's risk of progression to a diagnosis of Alzheimer’s was reduced by 58% one year into the study, and 36% at 2 years, but no risk reduction at the end of three years. Vitamin E was also tested in the study and was found to have no effect at any point in the study.
Petersen, R.C. et al. 2005. Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment. New England Journal of Medicine, 352 (23), 2379-2388.
A study using genetically engineered mice has found that those mice on a diet rich in curcumin (the yellow pigment in the curry spice turmeric) developed 85% few Alzheimer’s plaques then the control group. Curcumin has antioxidant, anti-inflammatory, and cholesterol lowering properties, and has long been used in India as treatment for a variety of ailments. A human trial involving 33 Alzheimer's patients will soon commence.
Yang, F., Lim, G.P., Begum, A.N., Ubeda, O.J., Simmons, M.R., Ambegaokar, S.S., Chen, P.P., Kayed, R., Glabe, C.G., Frautschy, S.A. & Cole, G.M. 2004. Curcumin inhibits formation of Abeta oligomers and fibrils and binds plaques and reduces amyloid in vivo. Journal of Biological Chemistry, published online ahead of print December 7, 2004A copy of the full paper can be found on the Journal of Biological Chemistry Web site athttp://tinyurl.com/5bzbs
A three-month study of 55 elderly patients with mild or moderate Alzheimer’s found that those given EV-1, a dietary supplement containing, among other things, the putative antioxidant ingredient of red wine, showed no deterioration during the trial. The supplement is designed to interfere with a defective mitochondrial cycle thought to contribute to the metabolic disturbances associated with late onset Alzheimer’s. The Krebs tricarboxylic acid cycle is fuelled by glucose and regulates levels of reactive oxygen species in the body. EV-1 contains glucose, a compound called malate that primes or maintains the Krebs cycle, and resveratrol - the antioxidant component of red wine that is thought to soak up reactive oxygen species. More studies are needed to confirm this result.
The findings were presented in November at the annual meeting of the Society for Neuroscience (SFN) in New Orleans.
An 11-week trial involving 54 young, healthy men and women engaging in an endurance training program, has found that markers for the production of new muscle mitochondria only increased in the group not taking vitamin C and E supplements. It’s possible that high doses of vitamins C and E act as antioxidants and take away some of the oxidative stress needed to develop muscular endurance.
A new study from the Women's Health Initiative has found that calcium and vitamin D supplements after menopause can improve women's cholesterol profiles, with much of that effect tied to raising vitamin D levels. Taking the calcium and vitamin D supplements was especially helpful in raising vitamin D levels in women who were older, women who had a low intake, women who had levels first measured in the winter, and women who didn’t smoke and who drank less alcohol.
A guinea pig study demonstrates that low levels of vitamin C during pregnancy have long-lasting effects on the child's hippocampus.
Like us, guinea pigs can’t make vitamin C, but must obtain it from their diet. This makes them a good model for examining the effects of vitamin C deficiency.
In a recent study looking specifically at the effects of prenatal vitamin C deficiency, 80 pregnant guinea pigs were fed a diet that was either high or low in vitamin C. Subsequently, 157 of the newborn pups were randomly allocated to either a low or high vitamin C diet (after weaning), creating four conditions: high/high (controls); high/low (postnatal depletion); low/high (postnatal repletion); low/low (pre/postnatal deficiency). Only males experienced the high/low condition (postnatal depletion).
Only the postnatal depletion group showed any effect on body weight; no group showed an effect on brain weight.
Nevertheless, although the brain as a whole grew normally, those who had experienced a prenatal vitamin C deficiency showed a significantly smaller hippocampus (about 10-15% smaller). This reduction was not reversed by later repletion.
This reduction appeared to be related to a significant reduction in the migration of new neurons into the dentate gyrus. There was no difference in the creation or survival of new neurons in the hippocampus.
This finding suggests that marginal deficiency in vitamin C during pregnancy (a not uncommon occurrence) may have long-term effects on offspring.
 Tveden-Nyborg P, Vogt L, Schjoldager JG, Jeannet N, Hasselholt S, Paidi MD, Christen S, Lykkesfeldt J. Maternal Vitamin C Deficiency during Pregnancy Persistently Impairs Hippocampal Neurogenesis in Offspring of Guinea Pigs. PLoS ONE [Internet]. 2012 ;7(10). Available from: http://dx.doi.org/10.1371/journal.pone.0048488
Full text is available at http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048488
A more rigorous measurement of diet finds that dietary factors account for nearly as much brain shrinkage as age, education, APOE genotype, depression and high blood pressure combined.
The study involved 104 healthy older adults (average age 87) participating in the Oregon Brain Aging Study. Analysis of the nutrient biomarkers in their blood revealed that those with diets high in omega 3 fatty acids and in vitamins C, D, E and the B vitamins had higher scores on cognitive tests than people with diets low in those nutrients, while those with diets high in trans fats were more likely to score more poorly on cognitive tests.
These were dose-dependent, with each standard deviation increase in the vitamin BCDE score ssociated with a 0.28 SD increase in global cognitive score, and each SD increase in the trans fat score associated with a 0.30 SD decrease in global cognitive score.
Trans fats are primarily found in packaged, fast, fried and frozen food, baked goods and margarine spreads.
Brain scans of 42 of the participants found that those with diets high in vitamins BCDE and omega 3 fatty acids were also less likely to have the brain shrinkage associated with Alzheimer's, while those with high trans fats were more likely to show such brain atrophy.
Those with higher omega-3 scores also had fewer white matter hyperintensities. However, this association became weaker once depression and hypertension were taken into account.
Overall, the participants had good nutritional status, but 7% were deficient in vitamin B12 (I’m surprised it’s so low, but bear in mind that these are already a select group, being healthy at such an advanced age) and 25% were deficient in vitamin D.
The nutrient biomarkers accounted for 17% of the variation in cognitive performance, while age, education, APOE genotype (presence or absence of the ‘Alzheimer’s gene’), depression and high blood pressure together accounted for 46%. Diet was more important for brain atrophy: here, the nutrient biomarkers accounted for 37% of the variation, while the other factors accounted for 40% (meaning that diet was nearly as important as all these other factors combined!).
The findings add to the growing evidence that diet has a significant role in determining whether or not, and when, you develop Alzheimer’s disease.
 Bowman G l, Silbert L c, Howieson D, Dodge HH, Traber M g, Frei B, Kaye JA, Shannon J, Quinn J f. Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology [Internet]. 2012 ;78(4):241 - 249. Available from: http://www.neurology.org/content/78/4/241.abstract
The newborn brain may be particularly vulnerable to vitamin C deficiency, which has been found in rodent studies to lead to a marked decrease in the number of brain cells in the hippocampus. Although there is no clear evidence that vitamin C supplements on their own improve memory or brain function in adults, two large studies of older adults have found that taking both vitamin C and vitamin E supplements significantly reduced the risk of Alzheimer's. Other indications suggest the efficacy of these vitamins may depend on whether they are taken in through food or through supplements (food is better), and whether the individual has the "Alzheimer's gene" (better not to).
It's been proposed that vitamin E might help prevent Alzheimer's, because of the role that oxidative stress plays in the development of the disease. Vitamin E is an antioxidant. It has been found in cultured cell studies that vitamin E does help protect against the effects of oxidative stress, and results in significantly fewer neurons dying. At the level of the organism, results are not so clearcut. One study of older adults found those eating the most vitamin E-rich foods had a lower risk of developing Alzheimer's, provided they didn't have the 'Alzheimer's gene'. Supplements did not have the same effect. Another, larger, study found that those with high intakes of vitamins E and C were less likely to develop Alzheimer's, regardless of gene status. This was especially true for smokers.
Research indicates that choline is a crucial ingredient in a pregnant woman's diet, for brain development in the fetus. Among older adults, choline, particularly in conjunction with omega-3 fatty acids and uridine (not available from food), has been found to improve memory in those cognitively impaired. Top sources of choline are eggs, peanuts, and meat. Fish and soy are also good sources. A choline food database is available at: www.nal.usda.gov/fnic/foodcomp
Research with rats indicates that increasing magnesium levels in the brain improves learning and memory, apparently through its effects on synaptic density and plasticity. Unfortunately, traditional supplements have little effect on magnesium levels in the brain, but the researchers developed a new compound that was effective. Magnesium deficits are common in the population of industrialized countries, and increase with age. Good sources of magnesium are dark green leafy vegetables (such as spinach), some nuts (almonds and cashews are particularly good), beans, seeds and whole unrefined grains (especially buckwheat). See here for a list of magnesium-rich foods.
Zinc has been linked to cognitive and motor function in very young children and adults, and one small study has found zinc supplements improved cognition, especially attention, in adolescents, who are particularly at risk of zinc deficiency. Red meats, fish and grains are good sources of zinc.
See the article on Mempowered
A study and a recent review suggest that while iron is important for brain health and development, whether it’s beneficial or harmful depends on the other nutrients consumed with it.
A study involving 676 children (7-9) in rural Nepal has found that those whose mothers received iron, folic acid and vitamin A supplementation during their pregnancies and for three months after the birth performed better on some measures of intellectual and motor functioning compared to offspring of mothers who received vitamin A alone. However, there was no significant benefit for those whose mothers received iron, folic acid and zinc (plus vitamin A), or multiple micronutrients.
A negative effect of adding zinc is consistent with other research indicating that zinc inhibits iron absorption. Interestingly, new “ground-breaking” research demonstrates further the complexity of iron’s effects on the body. The researcher argues that many neurodegenerative diseases (such as Alzheimer’s) are partly caused by poorly bound iron, and it is vital to consume nutrients which bind iron and prevent the production of the toxins it will otherwise produce.
Such nutrients include brightly-colored fruits (especially purple) and vegetables, and green tea.
It’s also argued that Vitamin C is only beneficial if iron is safely bound, and if it’s not, excess Vitamin C might be harmful.
 Christian P, Murray-Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole PM, LeClerq SC, Tielsch JM. Prenatal Micronutrient Supplementation and Intellectual and Motor Function in Early School-aged Children in Nepal. JAMA: The Journal of the American Medical Association [Internet]. Submitted ;304(24):2716 - 2723. Available from: http://jama.ama-assn.org/content/304/24/2716.abstract
 Kell DB. Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples. Archives of Toxicology [Internet]. 2010 ;84(11):825 - 889. Available from: http://www.springerlink.com/content/y444357h4j61120u/
Another study shows that older adults with low levels of vitamin D have higher levels of cognitive decline, particularly in executive function (but not attention).
Another study has come out showing that older adults with low levels of vitamin D are more likely to have cognitive problems. The six-year study followed 858 adults who were age 65 or older at the beginning of the study. Those who were severely deficient in vitamin D were 60% more likely to have substantial cognitive decline, and 31% more likely to have specific declines in executive function, although there was no association with attention. Vitamin D deficiency is common in older adults in the United States and Europe (levels estimated from 40% to 100%!), and has been implicated in a wide variety of physical disease.
 Llewellyn DJ, Lang IA, Langa KM, Muniz-Terrera G, Phillips CL, Cherubini A, Ferrucci L, Melzer D. Vitamin D and Risk of Cognitive Decline in Elderly Persons. Arch Intern Med [Internet]. 2010 ;170(13):1135 - 1141. Available from: http://archinte.ama-assn.org/cgi/content/abstract/170/13/1135
A study involving multiple sclerosis sufferers has found very high rates of vitamin D deficiency, and that higher levels of vitamin D3 and its byproducts were associated with better scores on cognitive tests (especially reasoning and planning), and less brain atrophy and fewer brain lesions.
A study involving 236 persons with multiple sclerosis has found that only 7% of those with secondary-progressive MS showed sufficient vitamin D in their blood, compared to 18.3% of patients with the less severe relapsing-remitting type, and that higher levels of vitamin D3 and its byproducts were associated with better scores on cognitive tests (especially reasoning and planning), and less brain atrophy and fewer brain lesions. Lower-than-normal vitamin D status is known to be associated with a higher risk of developing MS
The results were reported at the American Academy of Neurology's 62nd Annual Meeting in Toronto, April 10–17, 2010.
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