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      Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment

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          Vitamins and minerals have many functions in the nervous system which are important for brain health. It has been suggested that various different vitamin and mineral supplements might be useful in maintaining cognitive function and delaying the onset of dementia. In this review, we sought to examine the evidence for this in people who already had mild cognitive impairment (MCI). To evaluate the effects of vitamin and mineral supplementation on cognitive function and the incidence of dementia in people with mild cognitive impairment. We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group’s (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CENTRAL, CINAHL, LILACs, Web of Science Core Collection, ClinicalTrials.gov, and the WHO Portal/ICTRP, from inception to 25 January 2018. We included randomised or quasi‐randomised, placebo‐controlled trials which evaluated orally administered vitamin or mineral supplements in participants with a diagnosis of mild cognitive impairment and which assessed the incidence of dementia or cognitive outcomes, or both. We were interested in studies applicable to the general population of older people and therefore excluded studies in which participants had severe vitamin or mineral deficiencies. We sought data on our primary outcomes of dementia incidence and overall cognitive function and on secondary outcomes of episodic memory, executive function, speed of processing, quality of life, functional performance, clinical global impression, adverse events, and mortality. We conducted data collection and analysis according to standard Cochrane systematic review methods. We assessed the risk of bias of included studies using the Cochrane 'Risk of bias' assessment tool. We grouped vitamins and minerals according to their putative mechanism of action and, where we considered it to be clinically appropriate, we pooled data using random‐effects methods. We used GRADE methods to assess the overall quality of evidence for each comparison and outcome. We included five trials with 879 participants which investigated B vitamin supplements. In four trials, the intervention was a combination of vitamins B6, B12, and folic acid; in one, it was folic acid only. Doses varied. We considered there to be some risks of performance and attrition bias and of selective outcome reporting among these trials. Our primary efficacy outcomes were the incidence of dementia and scores on measures of overall cognitive function. None of the trials reported the incidence of dementia and the evidence on overall cognitive function was of very low‐quality. There was probably little or no effect of B vitamins taken for six to 24 months on episodic memory, executive function, speed of processing, or quality of life. The evidence on our other secondary clinical outcomes, including harms, was very sparse or very low‐quality. There was evidence from one study that there may be a slower rate of brain atrophy over two years in participants taking B vitamins. The same study reported subgroup analyses based on the level of serum homocysteine (tHcy) at baseline and found evidence that B vitamins may improve episodic memory in those with tHcy above the median at baseline. We included one trial (n = 516) of vitamin E supplementation. Vitamin E was given as 1000 IU of alpha‐tocopherol twice daily. We considered this trial to be at risk of attrition and selective reporting bias. There was probably no effect of vitamin E on the probability of progression from MCI to Alzheimer's dementia over three years (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study, moderate‐quality evidence). There was also no evidence of an effect at intermediate time points. The available data did not allow us to conduct analyses, but the authors reported no significant effect of three years of supplementation with vitamin E on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality (five deaths in each group). We considered this to be low‐quality evidence. We included one trial (n = 256) of combined vitamin E and vitamin C supplementation and one trial (n = 26) of supplementation with chromium picolinate. In both cases, there was a single eligible cognitive outcome, but we considered the evidence to be very low‐quality and so could not be sure of any effects. The evidence on vitamin and mineral supplements as treatments for MCI is very limited. Three years of treatment with high‐dose vitamin E probably does not reduce the risk of progression to dementia, but we have no data on this outcome for other supplements. Only B vitamins have been assessed in more than one RCT. There is no evidence for beneficial effects on cognition of supplementation with B vitamins for six to 24 months. Evidence from a single study of a reduced rate of brain atrophy in participants taking vitamin B and a beneficial effect of vitamin B on episodic memory in those with higher tHcy at baseline warrants attempted replication. Review question This review investigated whether people with mild cognitive impairment can reduce their risk of developing dementia, or can prevent their memory or other thinking skills from deteriorating further, by taking vitamin or mineral supplements. Background Slight changes in memory and thinking skills are common as people get older. When these changes are worse than can be expected in normal ageing, but are not bad enough to make a person's usual activities difficult to manage, then the person is said to have mild cognitive impairment (MCI). People with MCI are at increased risk of developing dementia in the future. Vitamins and minerals are naturally occurring substances which are needed in the diet to maintain health. They have lots of different functions in the body and many are essential to keep the brain working properly. It has been suggested that supplementing a person's normal diet with extra doses of these vitamins or minerals might help to maintain thinking skills or prevent dementia. Study characteristics We found eight randomised controlled trials (RCTs), which investigated four different types of vitamin or mineral pills by comparing them to a placebo (a dummy pill). The vitamins tested were B vitamins (vitamin B6, vitamin B12 and folic acid), vitamin E, and vitamin E and C given together. The only mineral tested was chromium. Key results and quality of the evidence Vitamin B combination versus placebo Five trials with a total of 879 participants compared B vitamins with placebo. Four used combinations of vitamin B6, vitamin B12, and folic acid; one small study tested folic acid on its own. None of these studies reported whether or not participants developed dementia. These studies did not find that memory or thinking skills differed between the group of people who took vitamin B supplements and those who took placebo after treatment lasting six months to two years. Our confidence in the results on different tests used in the studies varied from moderate to very low. Two years of vitamin B supplements did seem to help memory in a small subgroup of participants in one study who could be identified by a particular blood test at the start of the trial. One study found that there was probably no effect on participants' quality of life. One study scanned the brains of some participants and reported that B vitamins may slow the rate of brain shrinkage. Harmful effects and deaths were reported in very few participants and we cannot conclude whether or not there are harms from taking these or similar combinations of B vitamins. Vitamin E versus placebo. One study with 516 participants compared a relatively high dose of vitamin E (2000 IU a day) to placebo in people who were also taking a multivitamin containing 15 IU of vitamin E (the daily requirement for vitamin E is approximately 30 IU). The risk of developing dementia due to Alzheimer’s disease (the commonest form of dementia) is probably not affected by three years of treatment with high‐dose vitamin E. The quality of the evidence for other outcomes was lower, but there may also be no effect of this dose of vitamin E on specific memory or thinking skills or on how well people could manage their daily activities. Vitamin E and C versus placebo One study with 256 participants compared a combination of vitamins C and E with placebo. It found no effect on overall memory and thinking skills, but we had little confidence in this result because of the quality of the evidence. Chromium picolinate versus placebo Only one very small study with 26 participants investigated the effect of chromium supplements. This study was too small for us to be able to draw any conclusions. Conclusions The amount and quality of research evidence about vitamin and mineral supplements for treating MCI in people without nutritional deficiency is limited. At the moment, it is not possible to identify any supplements which can reduce the risk of people with MCI developing dementia or which can effectively treat their symptoms. More research is needed before we can answer our review question.

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          Most cited references 130

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          Vitamin E and donepezil for the treatment of mild cognitive impairment.

          Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease. In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function. A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers. Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo. Copyright 2005 Massachusetts Medical Society.
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            A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.

            Randomized trials have shown that low-dose aspirin decreases the risk of a first myocardial infarction in men, with little effect on the risk of ischemic stroke. There are few similar data in women. We randomly assigned 39,876 initially healthy women 45 years of age or older to receive 100 mg of aspirin on alternate days or placebo and then monitored them for 10 years for a first major cardiovascular event (i.e., nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes). During follow-up, 477 major cardiovascular events were confirmed in the aspirin group, as compared with 522 in the placebo group, for a nonsignificant reduction in risk with aspirin of 9 percent (relative risk, 0.91; 95 percent confidence interval, 0.80 to 1.03; P=0.13). With regard to individual end points, there was a 17 percent reduction in the risk of stroke in the aspirin group, as compared with the placebo group (relative risk, 0.83; 95 percent confidence interval, 0.69 to 0.99; P=0.04), owing to a 24 percent reduction in the risk of ischemic stroke (relative risk, 0.76; 95 percent confidence interval, 0.63 to 0.93; P=0.009) and a nonsignificant increase in the risk of hemorrhagic stroke (relative risk, 1.24; 95 percent confidence interval, 0.82 to 1.87; P=0.31). As compared with placebo, aspirin had no significant effect on the risk of fatal or nonfatal myocardial infarction (relative risk, 1.02; 95 percent confidence interval, 0.84 to 1.25; P=0.83) or death from cardiovascular causes (relative risk, 0.95; 95 percent confidence interval, 0.74 to 1.22; P=0.68). Gastrointestinal bleeding requiring transfusion was more frequent in the aspirin group than in the placebo group (relative risk, 1.40; 95 percent confidence interval, 1.07 to 1.83; P=0.02). Subgroup analyses showed that aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and myocardial infarction among women 65 years of age or older. In this large, primary-prevention trial among women, aspirin lowered the risk of stroke without affecting the risk of myocardial infarction or death from cardiovascular causes, leading to a nonsignificant finding with respect to the primary end point. Copyright 2005 Massachusetts Medical Society.
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              Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging.

               J. Lindsay (2002)
              A prospective analysis of risk factors for Alzheimer's disease was a major objective of the Canadian Study of Health and Aging, a nationwide, population-based study. Of 6,434 eligible subjects aged 65 years or older in 1991, 4,615 were alive in 1996 and participated in the follow-up study. All participants were cognitively normal in 1991 when they completed a risk factor questionnaire. Their cognitive status was reassessed 5 years later by using a similar two-phase procedure, including a screening interview, followed by a clinical examination when indicated. The analysis included 194 Alzheimer's disease cases and 3,894 cognitively normal controls. Increasing age, fewer years of education, and the apolipoprotein E epsilon4 allele were significantly associated with increased risk of Alzheimer's disease. Use of nonsteroidal anti-inflammatory drugs, wine consumption, coffee consumption, and regular physical activity were associated with a reduced risk of Alzheimer's disease. No statistically significant association was found for family history of dementia, sex, history of depression, estrogen replacement therapy, head trauma, antiperspirant or antacid use, smoking, high blood pressure, heart disease, or stroke. The protective associations warrant further study. In particular, regular physical activity could be an important component of a preventive strategy against Alzheimer's disease and many other conditions.

                Author and article information

                Cochrane Database of Systematic Reviews
                November 01 2018
                [1 ]Oxford Health NHS Foundation Trust; Elms Centre Oxford Road Banbury Oxfordshire UK OX16 9AL
                [2 ]Cognitive Treatment and Research Unit, Sussex Partnership NHS Foundation Trust; Old Age Psychiatry; Grove House Southfield Road Crowborough UK TN6 1HB
                [3 ]Sussex Partnership NHS Foundation Trust; Specialist Older People's Services; Uckfield Community Hosptial Framfield Road Uckfield UK TN22 5AW
                [4 ]Fondazione "Università G. D'Annunzio"; Centre for Systematic Reviews; Via dei Vestini 31 Chieti Chieti Italy 66100
                [5 ]University of Bern; Institute of Social and Preventive Medicine (ISPM); Mittelstrasse 43 Bern Bern Switzerland 3012
                [6 ]UK Cochrane Centre; Oxford UK
                [7 ]Newcastle University; NIHR Innovation Observatory; Suite A, 4th Floor, Time Central Gallowgate Newcastle Upon Tyne UK NE1 4BF
                [8 ]Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust; Department of Nutrition and Dietetics; Mindelsohn Way Edgbaston Birmingham West Midlands UK B15 2GW
                [9 ]Central Park Medical College; Community Medicine; Central Park Housing Scheme, Ferozepur Road, Kahna Nau Lahore Punjab Pakistan 53100
                [10 ]Faculty of Medicine, Akdeniz University; Department of Family Medicine; Antalya Turkey 07059
                [11 ]Brighton and Sussex Medical School, University of Brighton; Department of Medical Education (Postgraduate); Room 341, Mayfield House Falmer UK BN1 9PH
                [12 ]University "G. D'Annunzio" of Chieti-Pescara; Department of Medicine and Ageing Sciences; Via dei Vestini 31 Chieti Scalo Italy 66013
                [13 ]Universidad de Antofagasta; Faculty of Medicine and Dentistry; Avenida Argentina 2000 Antofagasta Chile 127001
                [14 ]Iberoamerican Cochrane Centre; Sant Antoni Maria Claret 167 Barcelona Spain 08025
                [15 ]Brighton and Sussex Medical School; Centre for Dementia Studies; Mayfield House, University of Brighton Falmer Brighton UK BN1 9PH
                © 2018


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