Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF et al.. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 300, 1774-1783

Department of Neurosciences, University of California, San Diego, 9500 Gilman Dr, M/C 0949, La Jolla, CA 92093, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 10/2008; 300(15):1774-83. DOI: 10.1001/jama.300.15.1774
Source: PubMed


Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B(6) and B(12). Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline.
To determine the efficacy and safety of B vitamin supplementation in the treatment of AD.
A multicenter, randomized, double-blind controlled clinical trial of high-dose folate, vitamin B(6), and vitamin B(12) supplementation in 409 (of 601 screened) individuals with mild to moderate AD (Mini-Mental State Examination scores between 14 and 26, inclusive) and normal folic acid, vitamin B(12), and homocysteine levels. The study was conducted between February 20, 2003, and December 15, 2006, at clinical research sites of the Alzheimer Disease Cooperative Study located throughout the United States.
Participants were randomly assigned to 2 groups of unequal size to increase enrollment (60% treated with high-dose supplements [5 mg/d of folate, 25 mg/d of vitamin B(6), 1 mg/d of vitamin B(12)] and 40% treated with identical placebo); duration of treatment was 18 months.
Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog).
A total of 340 participants (202 in active treatment group and 138 in placebo group) completed the trial while taking study medication. Although the vitamin supplement regimen was effective in reducing homocysteine levels (mean [SD], -2.42 [3.35] in active treatment group vs -0.86 [2.59] in placebo group; P < .001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-cog score during 18 months (0.372 points per month for placebo group vs 0.401 points per month for active treatment group, P = .52; 95% confidence interval of rate difference, -0.06 to 0.12; based on the intention-to-treat generalized estimating equations model), or on any secondary measures. A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements.
This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD. Identifier: NCT00056225.

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Available from: Ronald Thomas, Mar 04, 2015
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    • "The placebo decline not seen in mild subjects at 24 weeks was 2.9 ADAS-cog units at 50 weeks in the control arm, comparable to the mean placebo decline (3.5 ± 1.8 units [mean ± S.E.]) seen in a meta-analysis of studies in mild AD subjects at 12 months [28] [29] [30] [31] [32] [33] [34] [35] performed by two of the authors (CMW, DJW). By contrast, the mean decline seen in mild subjects receiving the 138 mg/day dose was close to zero, implying an effect size equivalent to 96% of the decline seen in the control arm and statistically significant (p = 0.009). "
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    ABSTRACT: Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: -5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.
    Full-text · Article · Dec 2014 · Journal of Alzheimer's disease: JAD
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    • "Recent RCTs on the effects of folate, vitamin B12, and vitamin B6 supplementation have been performed in subjects with mild to moderate AD. These failed in showing any effect of supplementation in slowing cognitive decline (Sun et al., 2007; Aisen et al., 2008; Malouf and Grimley Evans, 2008; Malouf and Areosa Sastre, 2009). A review on supplementation of vitamins B12, B6, and folic acid alone or in combination showed that results from nineteen RCTs did not appear to improve cognitive function in individuals with or without existing cognitive impairment (Ford and Almeida, 2012). "
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    ABSTRACT: Several chemical substances belonging to classes of natural dietary origin display protective properties against some age-related diseases including neurodegenerative ones, particularly Alzheimer's disease (AD). These compounds, known as nutraceuticals, differ structurally, act therefore at different biochemical and metabolic levels and have shown different types of neuroprotective properties. The aim of this review is to summarize data from observational studies, clinical trials, and randomized clinical trials (RCTs) in humans on the effects of selected nutraceuticals against age-related cognitive impairment and dementia. We report results from studies on flavonoids, some vitamins and other natural substances that have been studied in AD and that might be beneficial for the maintenance of a good cognitive performance. Due to the substantial lack of high-level evidence studies there is no possibility for recommendation of nutraceuticals in dementia-related therapeutic guidelines. Nevertheless, the strong potential for their neuroprotective action warrants further studies in the field.
    Full-text · Article · Jun 2014 · Frontiers in Pharmacology
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    • "Several micronutrients, in particular vitamins B6 and B12 and folic acid with their effect on homocysteine (Hcy) metabolism [6-8], as well as antioxidants [9,10], have been shown to be associated with cognitive decline. Nevertheless, whether supplementation with micronutrients is capable of reducing the risk of dementia remains controversial [11-14]. Only a few trials of micronutrient supplementation in those who are cognitively impaired have been reported [15-18]. "
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    ABSTRACT: Malnutrition is a widespread problem in elderly people and is associated with cognitive decline. However, interventional studies have produced ambiguous results. For this reason, we wanted to determine the effect of micronutrient supplementation on blood and tissue levels and on general nutritional status in persons with mild or moderate cognitive impairment. We performed a 2-month, open-label trial, administering a daily micronutrient supplement to 42 memory clinic patients with mild cognitive deficits. Blood levels of antioxidants, zinc, and B vitamins were determined before and after supplementation. In addition, we assessed metabolic markers for B vitamins and intracellular (buccal mucosa cell [BMC]) antioxidant levels. Nutritional status was assessed by using the Mini Nutritional Assessment (MNA). Blood levels of B vitamins, folic acid, lutein, beta-carotene, alpha-carotene, and alpha-tocopherol increased significantly. Decreases in homocysteine levels and the thiamine pyrophosphate effect and an increase in holotranscobalamin were observed. We found no increase in intracellular antioxidant levels of BMC. The MNA score in subjects at risk for malnutrition increased significantly, mainly owing to better perception of nutritional and overall health status. Micronutrient supplementation improved serum micronutrient status, with improved metabolic markers for B vitamins but not for intracellular antioxidant status, and was associated with improved self-perception of general health status. Our data underline the necessity of determining micronutrient status and support the use of additional assessments for general health and quality of life in nutritional supplementation trials.
    Full-text · Article · Nov 2013 · Nutrition Journal
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