Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment
Abstract
Background
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).
Objectives
To evaluate the effects of vitamin and mineral supplementation on cognitive function and the incidence of dementia in people with mild cognitive impairment.
Search methods
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.
Selection criteria
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.
Data collection and analysis
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.
Main results
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.
Authors' conclusions
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.
PICOs
Plain language summary
Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment
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.
Authors' conclusions
Summary of findings
| B vitamins compared to placebo for MCI | |||||
| Patient or population: MCI | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with B vitamins | ||||
| Incidence of dementia ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Overall cognitive function | MD with B vitamins was 0.44 MMSE points higher | 488 | ⊕⊝⊝⊝ | Due to the very low‐quality of the evidence, we cannot be sure of any effect of B vitamins on overall cognitive function. * 2 studies reported final score; 1 study reported change from baseline. From the 2 studies (n=150) which reported final scores, the mean MMSE with placebo was 26.97 points. | |
| Episodic memory | SMD with B vitamins was 0.09 higher | 397 | ⊕⊕⊕⊝ | B vitamins probably resulted in little to no difference in episodic memory. | |
| Executive function | SMD with B vitamins was 0.03 higher | 392 | ⊕⊕⊕⊝ | B vitamins probably resulted in little to no difference in executive function. | |
| Speed of processing | SMD with B vitamins was 0.04 higher | 173 | ⊕⊕⊕⊝ | B vitamins probably resulted in little to no difference in speed of processing. | |
| Quality of life | The mean quality of life was 3.5 points | MD 0 points | 138 | ⊕⊕⊕⊝ | B vitamins probably resulted in little to no difference in quality of life. |
| Mortality ‐ not reported | Reported by only one study (2/133 died in vitamin B group, 0/133 died in placebo group). | ‐ | ‐ | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded due to risk of bias. One study was at high risk of performance bias and at unclear risk of selection and detection bias. 2 Downgraded due to inconsistency. I2 = 87%. 3 Downgraded due to imprecision. 95% CI included little or no effect and small benefit of B vitamins. 4 Downgraded due to imprecision. 95% CI included small effects in either direction. 5 Downgraded due to imprecision. Result derived from one small study. aEpisodic memory assessed with Hopkins Verbal Learning Test, word learning and the Auditory Verbal Learning Test. bExecutive function assessed with CLOX, the Stroop test, and the Frontal Assessment Battery. cSpeed of processing assessed with Trail‐making Test A, digit cancellation, and the Digit‐Symbol Substitution Test. CLOX: Clock drawing executive test | |||||
| Vitamin E compared to placebo for MCI | |||
| Patient or population: MCI | |||
| Outcomes | Impact | № of participants | Certainty of the evidence |
| Incidence of dementia due to Alzheimer's disease | 76 cases in vitamin E group and 73 cases in placebo group (HR 1.02, 95% CI 0.74 to 1.41) | 516 | ⊕⊕⊕⊝ |
| Overall cognitive functioning | Single study reported no significant difference between groups in changes from baseline of MMSE or ADAS‐cog. Sample sizes not reported. | (1 RCT) | ⊕⊕⊝⊝ |
| Episodic memory | Single study reported no significant difference between groups. Sample size not reported. | (1 RCT) | ⊕⊕⊝⊝ |
| Executive functioning | Single study reported no significant difference between groups. Sample size not reported. | (1 RCT) | ⊕⊕⊝⊝ |
| Quality of life ‐ not measured | ‐ | ‐ | |
| Mortality | No significant difference in deaths reported between vitamin E, donepezil, and placebo groups during double‐blind phase of trial. | (1 RCT) | ‐ |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||
| GRADE Working Group grades of evidence | |||
| 1 Downgraded due to imprecision. 95% CI around hazard ratio included possible effect in both directions. 2 Downgraded due to imprecision. Single study. Sample size for this outcome not reported. 3 Downgraded due to risk of bias. High risk of bias due to incomplete outcome data and selective reporting. aEpisodic memory assessed using standardised composite z‐score incorporating ADAS immediate and delayed word‐recall scores and the New York University immediate and delayed paragraph‐recall scores. bExecutive function assessed using standardised composite z‐score incorporating the digits‐backward test, Symbol Digit Modalities Test, and number‐cancellation test. ADAS‐cog: Alzheimer's Disease Assessment Scale ‐ cognitive | |||
| Vitamin E + vitamin C compared to placebo for MCI | |||||
| Patient or population: MCI | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with vitamin E + vitamin C | ||||
| Incidence of dementia ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Overall cognitive function | The mean overall cognitive function was 26.6 points | MD 0.23 points higher | 256 | ⊕⊝⊝⊝ | Due to very low‐quality evidence, we cannot be sure of any effect of vitamin C + vitamin E on overall cognitive function. |
| Episodic memory ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Executive function ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Speed of processing ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Quality of life ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Mortality ‐ not reported | ‐ | ‐ | ‐ | ‐ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded due to risk of bias. Unclear risks of selection, performance, and attrition bias. 2 Downgraded due to indirectness. Inadequate definition of MCI. 3 Downgraded due to imprecision. Result from a single small study. MCI: Mild cognitive impairment | |||||
Background
Description of the condition
Mild cognitive impairment and dementia
Prior to the onset of dementia, there can be a prodromal (pre‐symptomatic) stage which is often termed 'mild cognitive impairment' (MCI). The category of MCI captures those individuals whose cognitive deficits are beyond those typically seen in normal ageing and who are at high risk of future dementia. Different criteria have been proposed to identify MCI, but, broadly speaking, MCI of the amnestic subtype is a state where individuals have subjective and objective memory impairment that is inconsistent with age, but normal global cognitive functioning, and normal performance in non‐memory cognitive domains. The main focus of these criteria is to detect memory problems due to prodromal Alzheimer’s disease (AD). However, not all forms of MCI evolve into AD dementia and, therefore, there have been calls for broader, more inclusive criteria. In 2003, an International Working Group (IWG) developed consensus criteria and expanded the definition of MCI to include objective and subjective impairments in any cognitive domain (Winblad 2004). The influential Petersen criteria have been similarly extended (Petersen 2004). In recent years, new criteria have been proposed for MCI due to AD, including the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) criteria for preclinical/prodromal states (Albert 2011), updated NIA‐AA research criteria (Jack 2018), and updated versions of the IWG criteria (Dubois 2014).
Dementia is a syndrome of cognitive and functional decline which is usually progressive and which involves impairment in more than one cognitive function, memory being the most commonly affected in the early stages. Other higher cortical functions such as orientation, comprehension, learning, language, and judgement are also often affected. In most cases, the onset of dementia and its subsequent progression is gradual. The cognitive deficits in the early stages of the illness are relatively mild, but still have an impact on the ability to perform some normal daily activities. As the syndrome progresses, people with dementia eventually become increasingly dependent on others for support with all activities of daily living.
Types of MCI and dementia
There are numerous different definitions of MCI, with different focus (e.g. nature of the neuropsychological impairment, such as memory or non‐memory (Matthews 2007); prevalence (Stephan 2007); and risk of progression to dementia (Matthews 2008). Further subdivisions can be made depending on the suspected underlying cause of the cognitive deficits (e.g. MCI due to AD and MCI due to vascular disease, termed 'vascular cognitive impairment no dementia' (VCIND)). Moreover, attempts have been made to develop new criteria to capture even earlier preclinical states including, for example, 'pre‐MCI' that captures individuals with impaired executive function and language, higher apathy scores, and lower left hippocampal volumes on brain imaging compared to normal controls (Duara 2011). There is no standard definition of MCI universally accepted for use in clinical trials (Stephan 2013), but adaptations of the criteria suggested by Petersen are commonly used (Petersen 1999).
Subtypes of dementia are distinguished by the underlying pathology. The four most common subtypes are Alzheimer's disease dementia (AD) (accounting for an estimated 60% to 70% of all dementia cases); vascular dementia (VaD); dementia with Lewy Bodies (DLB); and frontotemporal dementia (FTD). Accurate diagnosis of the subtypes may be difficult. Mixed pathology is common, with more than 80% of cases having some features of Alzheimer’s disease (Jellinger 2006; WHO 2012). However, the proportion of dementia attributable to Alzheimer’s disease reduces with age (Savva 2009).
Prevalence of MCI and dementia
In the UK Medical Research Council's population‐based Cognitive Function and Ageing Study (CFAS), when 18 different definitions of MCI were mapped, the range of prevalence estimates was found to be highly variable (0.1% to 42.0%), and conversion rates to dementia generally low (Stephan 2007). In general, prevalence and conversion rates in specialist settings have been reported to be higher than in population‐based studies (adjusted conversion rate from MCI to dementia 9.6% versus 4.9%) (Mitchell 2009).
The risk of dementia increases with age; according to a World Health Organization (WHO) report, only 2% to 10% of cases start before the age of 65 (WHO 2012). The same report estimated that there were 35.6 million people with dementia in the world in 2010, and that this figure would double every 20 years to reach 65.7 million in 2030 (WHO 2012). However, there is a degree of uncertainty about the expected increase in prevalence of dementia. Recent research in the UK (Matthews 2013) and Denmark (Christensen 2013) suggests that the age‐specific prevalence of dementia may be falling in developed countries, supporting the idea that there may be modifiable risk factors. Nevertheless, because of population ageing, the overall prevalence continues to rise.
Risk factors
Generally, risk factors for dementia can be divided into modifiable and non‐modifiable factors. The non‐modifiable risk factors include age, genetic factors, family history, gender (females are at higher risk), and Down syndrome. The modifiable factors are smoking, high cholesterol, stroke, hypertension, lack of physical activity, diabetes mellitus, obesity, and low educational level. Among the non‐modifiable risk factors, age has the greatest effect. It has been calculated that in people older than 65, the risk of AD (the commonest cause of dementia) doubles every five years (Launer 1999; McCullagh 2001; van den Berg 2012; van der Flier 2005). A pooled analysis of four prospective studies in Europe found the incidence rate of AD among people aged 90 and over to be 63.5/1000 person‐years (Launer 1999). Genetics plays a major role in early onset AD, but a lesser role in the much commoner late onset disease. Epidemiological evidence suggests that many of the modifiable risk factors (diabetes, midlife obesity, midlife hypertension, smoking, and physical inactivity) are risk factors for both AD and vascular disease, including vascular dementia (The World Alzheimer Report 2014; WHO 2012).
At present, there is no cure for any subtype of dementia, but identifying and targeting modifiable risk factors may offer opportunities to modify its onset and course. Research has been reported suggesting that cognitive stimulation, exercise, diet, and the management of vascular risk factors such as hypertension, diabetes, obesity, smoking, and physical inactivity may have an important role in prevention of AD (Lindsay 2002; Lourida 2013; Norton 2014; Wilson 2002). There is also some evidence in support of vitamin supplementation as a preventive strategy. For example, vitamin B12 and folate lower levels of homocysteine, which is believed to be toxic to neurones. Protective effects of vitamin D and vitamin E against AD have also been proposed (Annweiler 2012; Dysken 2014; Llewellyn 2010). Many minerals might have antioxidant properties and may also be beneficial in protecting against oxidative stress and free radical damage. Hence, an evaluation of the role of vitamins and minerals as protective and preventive agents in cognitive impairment is warranted (see Appendix 1).
Description of the intervention
This review focusses on RCTs investigating the effect of vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment. Vitamins are organic compounds that are essential for the normal physiological process in the body and play important roles in growth and development (Kennedy 2011). Minerals are inorganic elements that come from the earth; as nutrients, they have similar essential roles in normal physiology (Centers for Disease Control and Prevention 2014). All of these essential nutrients are available naturally in food, although deficiencies can occur due to inadequate dietary intake or a variety of disease states. Dietary supplements are any consumed products that aim to provide additional nutrients to those obtained from the usual diet.
How the intervention might work
Vitamins and minerals have multiple important roles in the physiology of the human body at cellular and tissue levels. Putative biological mechanisms for each are summarised briefly in Appendix 1.
There is a complex array of micronutrients which protect the brain in a variety of ways, including protection against damaging oxygen‐free radicals, and which are important in neurogenesis, gene expression, and enzyme and receptor control (Powell 2000). Failure of these important systems appears to be implicated in the occurrence of neural damage (van der Schaft 2013). Therefore, ensuring adequate vitamin and mineral levels in the body might enhance cognitive function.
Oxidative stress has been shown to be a damaging process leading to an imbalance between oxygen‐free radicals, and the anti‐oxidative defences and repair of oxidative damage to proteins, lipids, RNA, and DNA (Halliwell 1992; Halliwell 1999; Tabet 2001; Tabet 2002). In addition, the central nervous system (CNS) contains high levels of unsaturated fatty acids that are substrates for peroxidation reactions (Ogawa 1994). An important defence mechanism in the brain involves enzymatic antioxidants which, if mediated through the supplementation of micronutrients, may replenish the brain with synthetic antioxidants providing a therapeutic approach to reduce oxidative stress (Reiter 1995). This may be a useful adjunct in modifying risk factors in the pathogenesis of neurodegenerative disorders (Packer 1997).
Vitamins:
Vitamins have a wide range of roles in the central nervous system and hence may affect the pathophysiological processes underlying the dementias in numerous different ways. Vitamin A may be involved in the stabilisation of beta amyloid fibrils (Ono 2012). Vitamin D is a precursor of hormones required for calcium and phosphorus metabolism and also has a possible role in cognition in older adults (Przybelski 2007). Vitamin E is an antioxidant which provides protection against free radical damage (Farina 2012; Takatsu 2009). B vitamins, particularly vitamin B12 and folic acid, have a role in energy production and metabolism within the CNS. B vitamins have also been implicated in the production of nucleic acids and production and maintenance of myelin essential for good neuronal health (Kühnast 2013; Osiezagha 2013; Pawlak 2014; Powers 2003; The World Alzheimer Report 2014). See Appendix 1 for more detail of possible mechanisms.
Minerals:
Minerals, similarly, have a very wide range of functions. For example, some may be involved in neuronal gene expression and the secretion of neurotransmitters (Ozawa 2012; Rossom 2012). Potassium, calcium, and magnesium were reported to be protective against cognitive decline in a cohort of Japanese participants (Ozawa 2012). Selenium is a critical component of the enzyme glutathione peroxidase and has been shown to protect the CNS and immune system from oxidative damage by harmful free radicals (Berr 2012; Mehdi 2013; Smorgon 2004). See Appendix 1 for more detail of possible mechanisms.
Micronutrients may not be maximally effective if supplemented in isolation. There are some patented formulas consisting of complex mixtures of micronutrients which are claimed to work synergistically. These are sometimes marketed as licensed medical foods. These licensed medical foods are not covered in this set of reviews.
Why it is important to do this review
The prevalence and financial implications of dementia are such that small effects on cognitive decline or on the incidence of dementia may have a large impact on healthcare costs and the overall burden of dementia. Robust assessments are needed of the effect size of interventions and of the ‘dose’ and duration of intervention necessary to achieve an effect.
For individuals, fear of cognitive decline and dementia may be a powerful motivator to seek preventive interventions. Nutritional supplements and cognitive activities (e.g. computerised 'brain training' games), in particular, are subject to promotion by those with commercial interests. It is important for people to know whether time, effort, and money they might invest to prevent cognitive decline is likely to be well spent. Information about adverse effects is also important. Although nutritional and behavioural interventions are often perceived to be ‘low risk’, they are not necessarily without the potential to cause harm. For example, trials have found high doses of vitamin E to be associated with more adverse effects than placebo (Bjelakovic 2012; Brigelius‐Flohe 2007; Miller 2005).
People with MCI are interested in interventions which could prevent or delay further cognitive decline. In addition, this review will be of interest to clinicians providing care for people with MCI and to policy makers.
Objectives
To evaluate the effects of vitamin and mineral supplementation on cognitive function and the incidence of dementia in people with mild cognitive impairment.
Methods
Criteria for considering studies for this review
Types of studies
We included in the review randomised or quasi‐randomised controlled trials, published or unpublished, reported in any language. We included studies involving both randomised and non‐randomised trial arms, but we only considered results from the former. We included cross‐over studies, but extracted and analysed data from the first treatment period only.
Types of participants
We included the following population: people diagnosed with mild cognitive impairment (MCI) according to internationally accepted and validated criteria. We recorded definitions. Participants should have been reported to be free of dementia at baseline. Consequently, we included only trials which assessed cognitive function or dementia status with internationally accepted and validated instruments at baseline and follow‐up.
We excluded trials of participants with severe vitamin or mineral deficiency where the intervention given could correct these deficiencies.
Types of interventions
We included studies comparing the effects of the described vitamin and mineral supplements with control interventions that were not expected to have specific risk‐modifying effects. The control arms typically involved placebo or no intervention/usual care. The minimum treatment duration was set at 12 weeks. Experimental interventions could be single vitamin or mineral supplements or combination treatments with any of the supplements listed in Appendix 1. We excluded trials of vitamins or minerals given in combination with other unrelated compounds (e.g. amino acids, fatty acids, or medications) unless the effects of the vitamins and minerals could be isolated. For example, a trial evaluating the effects of vitamin A and C versus methionine would have been excluded, whereas a trial evaluating vitamin A and C with methionine versus methionine only would have been included. We included only orally‐administered supplements. There were no restrictions on dose.
Types of outcome measures
Primary outcomes
1. The incidence of all‐cause dementia (assessed using internationally accepted and validated criteria).
The main time point of interest was end of trial, defined as the time point with the longest follow‐up duration as measured from randomisation (see also section, Data extraction and management). Outcome data reported at other time points after randomisation were extracted and presented. For this outcome, the minimum follow‐up period was 12 months.
2. Overall cognitive functioning, measured with, for example, Alzheimer's Disease Assessment Scale‐cognitive subscale (ADAS‐cog); the Mini Mental State Examination (MMSE); Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); Cambridge Cognition Examination (CAMCOG).
Secondary outcomes
Secondary outcomes were any internationally accepted and validated measures of:
‐ specific cognitive functioning subdomain: episodic memory,
‐ specific cognitive functioning subdomain: executive functioning,
‐ specific cognitive functioning subdomain: speed of processing,
‐ quality of life, either generic or disease‐specific,
‐ clinical global impression,
‐ functional performance,
‐ number of participants experiencing one or more serious adverse events (SAE),
‐ mortality.
‐ biomarkers: where studies included validated biomarkers (e.g., beta‐amyloid or tau in cerebrospinal fluid, structural MRI or amyloid imaging) as well as cognitive outcomes, biomarker data were extracted.
Outcomes included in the 'Summary of findings' table
Critical effectiveness outcomes included in the 'Summary of findings' table for this review were incidence of dementia, all outcomes related to cognitive functioning, quality of life, and mortality.
Search methods for identification of studies
Electronic searches
We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group’s (CDCIG) specialised register on 25 January 2018.
ALOIS is maintained by the Information Specialists for the CDCIG, and contains studies that fall within the areas of dementia prevention, dementia treatment and management, and cognitive enhancement in healthy elderly populations. The studies are identified through:
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Monthly searches of a number of major healthcare databases: MEDLINE, Embase, CINAHL, PsycINFO and LILACS;
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Monthly searches of a number of trial registers: ISRCTN; UMIN (Japan's Trial Register); the WHO portal (which covers ClinicalTrials.gov; ISRCTN; the Chinese Clinical Trials Register; the German Clinical Trials Register; the Iranian Registry of Clinical Trials, and the Netherlands National Trials Register, plus others);
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Quarterly search of the Cochrane Library's Central Register of Controlled Trials (CENTRAL);
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Six‐monthly searches of a number of grey literature sources: ISI Web of Science Core Collection; Index to Theses; Australasian Digital Theses.
To view a list of all sources searched for ALOIS, see 'About ALOIS' on the ALOIS website (www.medicine.ox.ac.uk/alois).
Details of the search strategies run in healthcare bibliographic databases, used for the retrieval of reports of dementia, cognitive improvement, and cognitive enhancement trials, can be viewed in the ‘methods used in reviews’ section within the editorial information about the Cochrane Dementia and Cognitive Improvement Group.
We ran additional searches in MEDLINE, Embase, PsycINFO, CENTRAL, CINAHL, Web of Science Core Collection, LILACs, ClinicalTrials.gov, and the WHO Portal/ICTRP to ensure that the searches for each suite of reviews was as comprehensive and as up‐to‐date as possible to identify published, unpublished, and ongoing trials. The search strategies used for the retrieval of reports of trials can be seen in Appendix 2.
Searching other resources
We screened reference lists of all included trials. In addition, we screened reference lists of recent systematic reviews, health technology assessment reports, and subject‐specific guidelines identified through www.guideline.gov. The search was restricted to those guidelines meeting the 2013 inclusion criteria of the National Guideline Centre (NGC), published in this year or later.
We contacted experts in the field and companies marketing included interventions, in order to provide additional randomised trial reports that were not identified by the search.
Data collection and analysis
We used this protocol, alongside instructions for data extraction, quality assessment, and statistical analyses which were based on a generic protocol generated by the editorial board of CDCIG to guide this and another 11 reviews on modifiable risk factors (see Acknowledgements).
Selection of studies
If multiple reports described the same trial, we included all to allow complete extraction of the trial details.
We used crowdsourcing to screen the search results. Details of this method have been described here (http://www.medicine.ox.ac.uk/alois/content/modifiable‐risk‐factors). In brief, teams of volunteers performed a ‘first assess’ on the search results. The volunteers were recruited through the author team’s institutions. They screened the results using an online tool developed for Cochrane Embase project but tailored for this programme of work. The crowd decided, based on a reading of title and abstract, whether the citation was describing a randomised or quasi‐randomised trial, irrespective of the citations topic. The citations identified as possibly relevant by the crowd were then screened by the author team.
Data extraction and management
Two review authors, working independently, extracted trial information using a standardised and piloted extraction method, referring also to a guidance document. Discrepancies were resolved by discussion, or by the involvement of a third reviewer. Where possible, we extracted (as a minimum) the following information related to characteristics of participants, intervention, and study design:
Participant characteristics
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gender
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baseline age (range, median, mean)
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education (level and years of education)
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baseline cognitive function
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cognitive diagnostic status
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duration of cognitive symptoms, if any
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ethnicity
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Apo‐E genotype
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diabetes mellitus (yes/no)
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physical activity (as defined by the trialists).
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smoking (never/ever)
Intervention characteristics
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nature of the intervention/generic and trade name of intervention
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description of the control condition
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duration of treatment
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dosage and frequency
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any concomitant treatments
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treatment adherence
Methodological characteristics
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trial design (individual or cluster randomisation; parallel group, factorial or cross‐over design)
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number of participants
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outcome measures used
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duration of follow‐up, as measured from randomisation
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duration of follow‐up, as measured from end of treatment
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source of financial support
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publication status
If secondary outcome data were available at multiple time‐points within a given trial, we grouped them as follows: immediate (up to 12 weeks), short‐term (up to one year), medium‐term (one to two years) and longer‐term results (more than two years). For the primary outcome (all‐cause dementia), we considered only outcome data at one year of follow‐up or longer. Within these time periods, we extracted the latest available data reported by the study. For example, if a study reported data at six months, nine months and one year, we extracted and analysed only the one‐year data for the one‐year (short‐term) time point.
For dichotomous outcomes (such as incident dementia or mortality), we extracted from each trial the number of participants with each outcome at each time point.
For continuous outcomes, we extracted the number of participants in whom the outcome was measured, and the mean and standard deviation of the change from baseline for each outcome at each time point. If change‐from‐baseline data were not available, we extracted the mean value at each time point. When necessary, means and measures of dispersion were approximated from figures in the reports.
Whenever possible, we extracted intention‐to‐treat data, i.e. analysing all participants according to the group randomisation; if this was not available, then we extracted and reported data from available case analyses. If neither of these types of data were available, we considered data from 'per protocol' analyses. We contacted the trialists if we were unable to obtain the necessary data from the trial report.
Assessment of risk of bias in included studies
After completion of a standardised training session provided by AR, one member of the author team and one experienced reviewer provided by the editorial team independently assessed the risk of bias in each of the included trials using the Cochrane's 'Risk of bias' tool (Higgins 2011). We resolved disagreements by consensus. We assessed the risk of bias potentially introduced by suboptimal design choices with respect to sequence generation, concealment of allocation, blinding of participants and caregivers, blinded outcome assessment, selective outcome reporting, and incomplete outcome data, including the type of statistical analyses used (true intention‐to‐treat versus other analyses). The general definitions that were used are reported in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Measures of treatment effect
We expressed the measure of treatment effect for continuous outcomes as a mean difference if all included studies used the same outcome measure and as a standardised mean difference (SMD), defined as the between‐group difference in mean values divided by the pooled standard deviation (SD), if the same outcome was assessed with a variety of measurement scales. We expressed the treatment effect for dichotomous outcomes as a relative risk (RR).
Unit of analysis issues
We did not identify any cross‐over or cluster‐randomised trials for inclusion.
Dealing with missing data
Missing data in individual trials may put the study estimates of effects at a high risk of bias, and may lower the overall quality of the evidence according to GRADE (Higgins 2011). We dealt with missing data in our 'Risk of bias' assessments and evaluated attrition bias in stratified analyses of the primary outcomes (Appendix 2). We analysed the available information and did not contact authors with a request to provide missing information; nor did we impute missing data ourselves.
Assessment of heterogeneity
We examined heterogeneity in stratified analyses by trial, participant, and intervention characteristics, as outlined in the sections Data and analyses and Appendix 2.
Assessment of reporting biases
We identified too few trials to allow the use of funnel plots to explore reporting biases or other small study effects.
Data synthesis
We examined participants, interventions, and outcomes in the included trials in order to decide whether they were sufficiently similar for data to be pooled.
Where we considered it appropriate to pool data, we used standard inverse‐variance random‐effects meta‐analysis to combine outcome data across the trials at the end of trials (DerSimonian 1986); and, if possible, at least one additional time point (see Primary outcomes and Data extraction and management for definitions of time points). We visually inspected forest plots for the presence of heterogeneity and calculated the variance estimate tau² as a measure of between‐trial heterogeneity (DerSimonian 1986). We prespecifed a Tau² of 0.04 to represent low heterogeneity, 0.09 to represent moderate heterogeneity, and 0.16 to represent high heterogeneity between trials (Spiegelhalter 2004). We also presented the I² statistic and the corresponding Chi² test (Higgins 2003). I² describes the percentage of variation across trials attributable to heterogeneity rather than to chance, with values of 25%, 50%, and 75% typically being interpreted as low, moderate, and high between‐trial heterogeneity. We preferred Tau² over I² in the interpretation of between‐trial heterogeneity, as the interpretation of I² can be largely affected by the precision of trials included in the meta‐analysis (Rücker 2008). We did statistical analyses in Review Manager 5 (RevMan 2014) and in STATA, release 13 (StataCorp, College Station, Texas).
Subgroup analysis and investigation of heterogeneity
We had prespecified the following trial characteristics as of interest for exploring possible heterogeneity: concealment of allocation, blinding of participants, blinded outcome assessment, intention‐to‐treat analysis, trial size (based on power calculation for trial primary outcome), duration of treatment (<3, 3‐12, >12 months), and length of follow‐up from randomisation (<3 months, 3‐12 months, >1‐2 years, >2 years). We had also prespecified the following possible clinical effect modifiers: age (40‐65 or >65 years), comorbidities, concomittant medications, and ethnicity (Dawson‐Hughes 2004). However, too few studies were included to allow us to conduct subgroup analyses or explore the effect of these features. Because B vitamins may work by lowering homocysteine levels and therefore may be more effective in participants with high homocysteine levels at baseline, we decided to amend the protocol to report the effects of B vitamins in subgroups of participants distinguished by level of homocysteine at baseline, where this was reported in the included studies (see Differences between protocol and review).
Sensitivity analysis
We had prespecified a sensitivity analysis for the primary effectiveness outcome, including high‐quality trials only. However, too few trials were included for this to be done.
GRADE and summary of findings table
We used GRADE to describe the quality of the overall body of evidence for each outcome in the 'Summary of findings' table (Higgins 2011; Guyatt 2008).
Quality in GRADE is defined as the degree of confidence which can be placed in the estimates of treatment benefits and harms. There are four possible ratings: 'high', 'moderate', 'low' and 'very low'. Rating evidence as 'high‐quality' implies that we are confident in our estimate of the effect, and further research is very unlikely to change this. A rating of 'very‐low' quality implies that we are very uncertain about the obtained summary estimate of the effect.
The GRADE approach rates evidence from RCTs which do not have serious limitations as 'high‐quality'. However, several factors can lead to the downgrading of the evidence to 'moderate', 'low' or 'very low'. The degree of downgrading is determined by the seriousness of these factors: study limitations (risk of bias); inconsistency; indirectness of evidence; imprecision; and publication bias (Higgins 2011; Guyatt 2008; Chandra 2001).
Results
Description of studies
Results of the search
We conducted searches in December 2014, July 2015, March 2016, August 2016, March 2017, and January 2018. In total, we retrieved 7,257 records from the six searches. After de‐duplication, 5211 records remained. A Crowd and the CDCIG information specialist assessed these at title and abstract level. In total, 725 results remained after this assessment. The review team then screened these records. Of these, we assessed 110 full‐text articles describing 67 trials for eligibility and included eight trials in the review (one after the authors provided subgroup data). Three trials, one described in three papers, were placed in the section 'Awaiting classification'; we sought information from the authors of these trials but received none. We identified one ongoing study of vitamin D supplementation which was due to be completed in July 2018. This process is depicted in Figure 1.
Study flow diagram.
Included studies
We identified eight studies eligible for inclusion in this review. For full details see Characteristics of included studies.
We grouped the studies into four comparisons. Five studies compared B vitamins to placebo (de Jager 2012, Eussen 2006, Fan 2017, Ting 2017, van Uffelen 2008). One study compared vitamin E to placebo (Petersen 2005), one compared vitamin E + vitamin C to placebo (Naeini 2014), and one compared chromium picolinate to placebo (Krikorian 2010).
Appendix 3 shows the supplement doses used in the studies in relation to the mean daily intake from food and the recommended daily intake for adults in the UK.
Comparison 1: B vitamins versus placebo ‐ description of studies
Five studies with 879 randomised participants contributed data to this comparison.
Setting
The studies were conducted in the UK, the Netherlands (2 studies), China and Singapore. Eussen 2006 included participants living in the community or in a care home; participants in all other studies were resident in the community.
Participants
All studies specifically excluded participants with dementia. de Jager 2012, Fan 2017 and van Uffelen 2008 used broadly similar criteria for MCI, which included a memory complaint and scores within a specified range on scales of cognition and daily functioning. Participants in Eussen 2006 had a Clinical Dementia Rating (CDR) global score of 0 or 0.5; for this review we, used data from the participants with a CDR score of 0.5. All participants in Ting 2017 had recent lacunar stroke and cognitive impairment ‐ no dementia (CIND); the cognitive impairment was defined as scoring at least 1.5 SDs below expected in at least one domain of a neuropsychological test battery.
All participants in Eussen 2006 met the authors' criteria for mild B12 deficiency.
Four studies had age‐based inclusion criteria: de Jager 2012 and Eussen 2006 only included participants aged 70 or older, Fan 2017 only included participants aged 60 to 75 years, and van Uffelen 2008 included participants aged 70 to 80 years. Across all studies, the mean age of participants ranged from approximately 66 years (Fan 2017) to approximately 80 years (Eussen 2006).
Interventions
All studies were placebo‐controlled. The experimental interventions varied in composition and dose.
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Participants in de Jager 2012 received 0.5 mg B12 + 0.8 mg folic acid + 20 mg B6 once daily for two years.
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Eussen 2006 was a three‐arm study. For this review, we combined the groups receiving 1 mg B12 and 1 mg B12 + 0.4 mg folic acid into a single experimental intervention group. Treatment was once daily for 24 weeks.
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Participants in Fan 2017 received 0.4 mg folic acid once daily for six months.
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Participants in Ting 2017 received 0.5 mg B12 + 2 mg folic acid + 25 mg B6 once daily for one to five years.
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Participants in van Uffelen 2008 received 0.4 mg vitamin B12 + 5 mg folic acid + 50 mg vitamin B6 once daily for a year. This study also investigated the effect of aerobic exercise in a 2 x 2 factorial design. For the purposes of this review, we combined data for all participants receiving vitamin B supplementation or placebo (i.e. with or without aerobic exercise) into single experimental and control groups.
Outcomes
None of the studies reported on our primary outcome of incidence of all‐cause dementia (although diagnosis of dementia by DSM‐IV was listed as a secondary outcome in the protocol for de Jager 2012).
Four of the five studies measured overall cognitive function with the MMSE (de Jager 2012, Fan 2017, Ting 2017, van Uffelen 2008).
We were able to extract data on episodic memory from three studies, which assessed delayed recall on the Hopkins Verbal Learning Test (de Jager 2012), word learning (Eussen 2006) and the Auditory Verbal Learning Test (van Uffelen 2008). We extracted data on executive function from four studies, which used CLOX (de Jager 2012), the Stroop test (Eussen 2006; van Uffelen 2008) and the Frontal Assessment Battery (Ting 2017). We extracted data on speed of processing from three studies, which used Trail‐making Test A (Eussen 2006), digit cancellation (Ting 2017), and the Digit‐Symbol Substitution Test (van Uffelen 2008).
Only van Uffelen 2008 reported on quality of life, using the dementia‐specific D‐QOL scale.
de Jager 2012 reported overall clinical impression using global CDR scores.
Fan 2017 reported functional performance on a 14‐item Chinese ADL scale.
de Jager 2012 reported efficacy results separately for participants with high or low total homocysteine (tHCy) (based on the median values at baseline). However, it was possible to calculate results for the whole experimental intervention and control groups from the reported means and standard deviations. van Uffelen 2008 reported results for men and women separately in each group, but some of the outcomes were reported in enough detail to allow us to combine the data for men and women.
Data on adverse events were reported by de Jager 2012 and van Uffelen 2008.
Comparison 2: Vitamin E versus placebo ‐ description of study
One study with 769 participants investigated this comparison (Petersen 2005). The study also had a donepezil arm. The primary outcome of the study was time to development of possible or probable Alzheimer's disease.
Setting
The study took place at 69 Alzheimer's Disease Cooperative Study (ADCS) sites in the US and Canada.
Participants
Participants were aged 55 to 90 years and had amnestic MCI of a degenerative nature (insidious onset and gradual progression). Specific cognition‐related inclusion criteria were impaired memory, a logical memory delayed‐recall score approximately 1.5 to 2 SD below an education‐adjusted norm and a score of 24 to 30 on the MMSE, as well as a CDR global score of 0.5.
Intervention
The experimental group of interest to this review received 2000 IU vitamin E (1000 IU twice daily), placebo donepezil, and a multivitamin (containing 15 IU of vitamin E) for three years. The comparator group received placebo vitamin E, placebo donepezil and the same multivitamin. Any participant who met clinical criteria for Alzheimer's disease at any time in the study was offered open‐label donepezil until study completion.
Outcomes
The study assessed progression to possible or probable Alzheimer's disease. Overall cognitive function was assessed with the MMSE and with a composite score derived from a battery of individual neuropsychological tests. Composite scores of interest to this review were also derived for the domains of memory and executive function (and additional composites for language and visuospatial function). Clinical global impression was assessed using the Global Deterioration Scale (GDS) and the CDR. Functional performance was assessed using the ADCS Mild Cognitive Impairment ADL Scale. Data on individual adverse events were reported by treatment group if they occurred in at least 5% of subjects in the donepezil or vitamin E group and at least two times in the placebo group during the double‐blind phase. The number of deaths in each treatment group was also reported.
Comparison 3: Vitamin E + vitamin C versus placebo ‐ description of study
One study investigated this comparison (Naeini 2014). It reported data on the 256 participants who completed the study (out of 296 who were randomised).
Setting
The study took place at a single centre in Iran with participants recruited from community clubs for retired people.
Participants
Dementia was listed as an exclusion criterion, but there was no information on how this was applied. Participants were defined as having MCI and identified as eligible for inclusion on the basis of a score of 21 to 26 on the validated Iranian version of the MMSE. We considered this not to be an adequate definition of MCI. However, we decided to include the study, downgrading the result for indirectness in relation to our review question.
Intervention
The experimental intervention was 300 mg vitamin E (DL‐alpha‐tocopherol) + 400 mg vitamin C once daily for one year. The comparator was placebo.
Outcome
The only outcome of interest to this review was overall cognitive functioning assessed with the MMSE.
Comparison 4: Chromium picolinate versus placebo ‐ description of study
One small study with 26 participants contributed data to this comparison (Krikorian 2010).
Setting
This single centre study recruited participants via community advertisement.
Participants
Participants had a global rating of 0.5 on the CDR.
Intervention
The experimental intervention was chromium picolinate containing 1000 mcg elemental chromium once daily for 12 weeks. The comparator was placebo.
Outcome
The only outcome of interest to this review was episodic memory assessed with the California Verbal Learning Test (CVLT).
Excluded studies
The Characteristics of excluded studies table shows the reasons for exclusion of 55 studies which were assessed in full text. The most common reasons for exclusion were the wrong population (participants did not have MCI) or the wrong intervention (included additional components or was given for less than 12 weeks).
Three studies are awaiting classification. In all three cases, we have been unable to obtain additional information from the authors at the time of writing. No results were available from one study. Results from the other two trials have been published, but we considered that essential information on various details of the methods, sample sizes, or results was missing.
We identified one ongoing trial of vitamin D supplementation which, according to the trial register, was due to be completed in July 2018.
Risk of bias in included studies
We describe the risk of bias of the included studies in the table, Characteristics of included studies. Our 'Risk of bias' judgments are also depicted in the 'Risk of bias' summary and 'Risk of bias' graph (Figure 2 and Figure 3).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Three studies (de Jager 2012, Petersen 2005, Ting 2017) provided enough information to judge the risk of selection bias to be low. The remaining five studies provided insufficient information on randomisation methods so we judged them to be at unclear risk of selection bias.
Blinding
Fan 2017 was an open‐label study which we judged to have a high risk of performance bias and an unclear risk of detection bias. There was also a lack of information about blinding from Krikorian 2010 and Naeini 2014. The other studies were at low risk of bias in this domain.
Incomplete outcome data
The longer studies ‐ Petersen 2005 and Ting 2017 ‐ lost high numbers of participants to follow‐up and we considered them to be at high risk of attrition bias by the end of the study. We judged the risk of attrition bias in Naeini 2014 to be unclear due to a lack of information on the group allocation of those who dropped out. The risk was also unclear in Krikorian 2010, where there was no information about whether or not there were any missing data. The remaining studies were at low risk of bias in this domain.
Selective reporting
We judged there to be a high risk of reporting bias in two studies. de Jager 2012 mentioned a number of outcomes in the protocol, including some relevant to this review, which were not reported. Petersen 2005 reported composite z‐scores rather than individual test results and did not report the number of participants in each analysis. Ting 2017 may have selected only some cognitive results from a larger neuropsychological test battery; we judged its risk of reporting bias to be unclear. We judged the risk in the other studies to be low, although for some studies there was no protocol and this judgement was based on the outcomes mentioned in the Methods sections of the papers being fully reported.
Other potential sources of bias
We found no other obvious sources of bias and rated this risk as low for all studies.
Effects of interventions
See: Summary of findings for the main comparison B vitamins compared to placebo for MCI; Summary of findings 2 Vitamin E compared to placebo for MCI; Summary of findings 3 Vitamin E + vitamin C compared to placebo for MCI
Comparison 1: B vitamins (folic acid, B12, B6) versus placebo
Five studies contributed data to this comparison (de Jager 2012; Eussen 2006; Fan 2017; Ting 2017; van Uffelen 2008).
Ting 2017 differed significantly from the other studies in recruiting only participants who had a recent history of lacunar stroke and in following them up for up to five years. In our primary analyses, in order to maximise comparability with the other studies, we included data from the one‐year outcome point from Ting 2017, but we considered the population as a potential source of heterogeneity. We also reported the results of this study at later time points, although these were all associated with substantial loss of participants from follow‐up.
de Jager 2012 reported the data for participants with higher (above median) baseline total homocysteine (tHcy) and lower baseline total homocysteine levels separately. For the primary analyses, we combined these groups. However, we also reported and commented on their subgroup data.
van Uffelen 2008 reported results separately for men and women; we have combined these data where we incorporated them in meta‐analyses.
Primary outcomes
Incidence of all‐cause dementia
No study reported the incidence of all‐cause dementia.
Overall cognitive functioning
Four studies used the MMSE to assess overall cognitive functioning (de Jager 2012; Fan 2017; Ting 2017; van Uffelen 2008). It is unknown what would constitute an important difference in MMSE score in this population. It is unlikely that MMSE is sensitive to small changes in cognition in people with MCI. We pooled data from three studies which reported MMSE in the form of mean score with standard deviation in each treatment group.
van Uffelen 2008 presented MMSE results as medians with interquartile ranges (IQR) for men and women separately. After 12 months of treatment, the median (IQR) MMSE score among men was 28 (27 to 30) in the vitamin group and 29 (28 to 29) in the placebo group. For women, the median (IQR) MMSE score was identical in both vitamin and placebo groups: 29 (27 to 30).
The pooled analysis of MMSE scores from the other three studies after six to 24 months was inconclusive due to imprecision; although the result slightly favoured B vitamins, we could not exclude the possibility of there being little or no effect (MD 0.44, 95%CI ‐0.23 to 1.12, 3 studies, 488 participants; Analysis 1.1, Figure 4). There was high heterogeneity in this analysis (I2 = 87%). This appeared to be due to a beneficial effect of B vitamins on MMSE score in Fan 2017, which was the only open‐label (unblinded) study. We considered the evidence behind this result to be very low‐quality because of the imprecision, study limitations, and inconsistency.
Forest plot of comparison: 1 B vitamins versus placebo, outcome: 1.1 Overall cognitive function (MMSE).
de Jager 2012 reported the data separately for participants with higher and lower baseline total homocysteine (tHcy). The results in these subgroups were also imprecise: higher baseline tHcy (MD 0.70, 95% CI ‐0.16 to 1.56; participants = 111); lower baseline tHcy (MD ‐0.30, 95% CI ‐1.10 to 0.50; participants = 112).
Ting 2017 did not find any significant effect of B vitamins on MMSE at any later time point (up to five years).
Secondary outcomes
Specific cognitive functioning subdomain: episodic memory
We pooled data on episodic memory from three studies (de Jager 2012; Eussen 2006; van Uffelen 2008). All used tests which involved delayed recall of word lists. There was probably little or no effect of six to 24 months of B vitamin supplementation on episodic memory (SMD 0.09, 95% CI ‐0.10 to 0.29; 3 studies, 397 participants; Analysis 1.2; Figure 5). Heterogeneity was low (I2 = 0%). We considered this to be moderate‐quality evidence, downgraded due to imprecision.
Forest plot of comparison: 1 B vitamins versus placebo, outcome: 1.2 Episodic memory.
In de Jager 2012, there was better episodic memory after 24 months in the group treated with vitamin B than in the group treated with placebo among participants with higher baseline tHCy (MD 1.30, 95% CI 0.02 to 2.58; participants = 111), but episodic memory did not differ significantly between intervention groups among participants with lower baseline tHcy (MD ‐0.30, 95% CI ‐1.58 to 0.98; participants = 112). The authors had analysed this outcome by logistic regression at five time points, starting from the 3rd month of the study, and estimated that after two years of the vitamin B intervention, participants taking vitamin B had a 69% higher likelihood of correct word‐recall than those taking placebo (OR 1.69, P = 0.001) (de Jager 2012).
Specific cognitive functioning subdomain: executive functioning
Four studies assessed executive functioning using three different measures (de Jager 2012; Eussen 2006; Ting 2017; van Uffelen 2008). We used CLOX‐1 data from the CLOX test and 'task 3' from the Stroop Colour‐Word Test. Ting 2017 reported only change‐from‐baseline data, so we were unable to pool these with data from the other studies. There was probably little or no effect of six to 24 months of B vitamin supplementation on executive functioning (SMD 0.03, 95% CI ‐0.23 to 0.29; 3 studies, 392 participants; Analysis 1.3; Figure 6). Heterogeneity was modest (I2 = 30%). We considered this to be moderate‐quality evidence, downgraded due to imprecision. Ting 2017 reported no significant difference between B vitamin and placebo groups on change from baseline in the Frontal Assessment Battery at any time point from one to five years.
Forest plot of comparison: 1 B vitamins versus placebo, outcome: 1.3 Executive function.
From de Jager 2012, there was no evidence of a difference in CLOX‐1 score between intervention groups among participants with either higher baseline tHcy (MD 0.30, 95% CI ‐0.50 to 1.10; participants = 111) or lower baseline tHCy (MD 0.50, 95% CI ‐0.13 to 1.13, participants = 112).
Ting 2017 did not find any significant effect of B vitamins on executive functioning at any later time point (up to five years).
Specific cognitive functioning subdomain: speed of processing
Three studies assessed speed of processing using three different measures (Eussen 2006; Ting 2017; van Uffelen 2008). Again, we were unable to include data from Ting 2017 in the meta‐analysis because only change‐from‐baseline data were available. There was probably little or no effect of six to 24 months of B vitamin supplementation on speed of processing (SMD 0.04, 95% CI ‐0.26 to 0.34; 2 studies, 173 participants; Analysis 1.4; Figure 7). Heterogeneity was low (I2 = 0%). We considered this to be moderate‐quality evidence, downgraded due to imprecision. Ting 2017 reported no significant difference in change‐from‐baseline of speed of processing (digit cancellation) between B vitamin and placebo groups at any time point from one to five years.
Forest plot of comparison: 1 B vitamins versus placebo, outcome: 1.4 Speed of processing.
Ting 2017 did not find any significant effect of B vitamins on speed of processing at any later time point (up to five years).
Quality of life, either generic or disease‐specific
One study (van Uffelen 2008) reported dementia‐specific quality of life using D‐QOL.There was no evidence of any effect of B vitamins after one year (MD 0, 95% CI ‐0.1 to 0.1; 1 study, 138 participants; Analysis 1.5). We considered this to be moderate‐quality evidence, downgraded due to imprecision.
Clinical global impression
de Jager 2012 assessed overall clinical state using CDR. The authors reported that "(i)n the whole intention‐to‐treat cohort, there was no significant effect of B vitamins on CDR (P = 0.23)", nor was there a significant interaction with baseline tHcy split by median. However, when they stratified tHcy by quartiles, they noted a significant benefit of B vitamins on CDR in the quartile with the highest tHcy at baseline (P = 0.039, Fisher's exact test). In this subgroup, they calculated that "the odds of having CDR=0 at follow‐up is five times greater in the active‐treatment group compared with placebo (P = 0.02)." It was not clear whether or not this was a prespecified analysis.
Functional performance
One study (Fan 2017) assessed functional performance using a 14‐item ADL scale (range of possible scores 14 to 56, with a lower score representing a better outcome). There may be a small beneficial effect of B vitamins on functional performance after six months (MD ‐0.78, 95% CI ‐1.35 to ‐0.21; 1 study, 75 participants; Analysis 1.6). We considered this to be very low‐quality evidence, downgraded due to imprecision and very serious concern about study limitations.
Number of participants experiencing one or more serious adverse events (SAE)
Two papers reported adverse events. van Uffelen 2008 reported minor adverse events in 3/179 randomised participants (2 in B vitamins group, 1 in placebo group). de Jager 2012 reported 242 adverse events in total in the B vitamins group (n = 133) and 271 in the placebo group (n = 133) over two years.
Mortality
de Jager 2012 reported two deaths in the B vitamins group (2/133) but none in the placebo group (0/133). No deaths were reported by the other studies.
Biomarkers
de Jager 2012 reported the rate of brain atrophy measured by MRI. Out of 133 participants who started treatment in each group, 85 in the vitamin and 83 in the placebo group had serial MRI scans which were technically suitable for analysis. After adjustment for age, the rate of brain atrophy per year was reported to be 29.6% lower in the active treatment group (0.76%, 95% CI 0.63 to 0.90) than in the placebo group (1.08%, 95% CI 0.94 to 1.22) (P = 0.001).
Comparison 2: Vitamin E versus placebo
One study with 516 participants contributed data for this comparison (Petersen 2005).
Sample sizes for change scores were not reported for some outcomes, making it impossible to re‐analyse the data without imputation of sample sizes. It was difficult to tell how the study had treated the missing data arising from participants who discontinued the study during the double‐blind phase (reported as 72 in the vitamin E group and 66 from the placebo group), and participants who had developed Alzheimer’s Disease by 36 months and had therefore been transferred to an open‐label phase for treatment with donepezil (76 participants in the vitamin E group and 73 in the placebo group).
A z‐score was calculated for cognitive domain scores. Positive numbers on this score indicated better outcomes.
Primary outcomes
Incidence of all‐cause dementia
The study did not report the incidence of all‐cause dementia, but did report the incidence of Alzheimer's dementia. By 12 months, 33 participants in the vitamin E group and 38 in the placebo group had progressed to Alzheimer's dementia. By 36 months, these numbers were 76 and 73 respectively. There was no significant difference between vitamin E and placebo groups in the probability of progression from MCI to Alzheimer's dementia over 36 months based on Cox analysis (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study) (Petersen 2005). There was also no significant difference between groups at any of the six‐monthly time points between baseline and 36 months (prespecified analyses). We considered this to be moderate‐quality evidence, downgraded due to imprecision.
Overall cognitive functioning
This was measured using MMSE and ADAS‐Cog at a six‐monthly interval from baseline for three years. At 36 months, the change from baseline in MMSE score (range 0 to 30, a higher score was better) was ‐2.20 ± 3.64 in the vitamin E group and ‐2.75 ± 4.04 in the placebo group. This was reported not to be statistically significant. We were not able to calculate the mean differences since sample sizes were not reported. There was also reported to be no significant difference in the change from baseline for ADAS Cog (modified) score (range 0 to 85, a higher was worse); this was 3.98 ± 7.56 in the vitamin E group and 3.72 ± 8.54 in the placebo group. We considered this to be low‐quality evidence, downgraded due to risk of bias and imprecision (single study, estimated sample size).
Secondary outcomes
We considered the evidence on all of the secondary outcomes reported here to be low‐quality, downgraded due to risk of bias and imprecision (single study, estimated sample size in each analysis).
Specific cognitive functioning subdomain: episodic memory
The study reported the change from baseline in a standardised z‐score for a memory domain, incorporating ADAS‐cog immediate and delayed word‐recall scores and the New York University immediate and delayed paragraph‐recall scores. Positive numbers indicated improvement. At 36 months, the change from baseline was ‐0.31 ± 0.59 in the vitamin E group and ‐0.28 ± 0.62 in the placebo group. This was reported not to be statistically significant. Sample size was not reported.
Specific cognitive functioning subdomain: executive functioning
The study reported the change from baseline in a standardised z‐score for an executive function domain, incorporating the Digits‐Backward test, Symbol Digit Modalities test, and Number‐Cancellation test. Positive numbers indicated improvement. At 36 months, the change from baseline was ‐0.19 ± 0.48 in the vitamin E group and ‐0.19 ± 0.53 in the placebo group. This was reported not to be statistically significant. Sample size was not reported.
Specific cognitive functioning subdomain: speed of processing
Not reported in the study.
Quality of life, either generic or disease‐specific
Not reported in the study.
Clinical global impression
The study reported the change in Global Deterioration Scale (range 0 to 7, higher was worse) from baseline to 36 months (0.64 ± 0.96 in the vitamin E group, 0.56 ± 0.99 in the placebo group). The number of participants in the analysis was not reported. This difference was described as not statistically significant in the study report.
Functional performance
This was measured with the Activities of Daily Living Scale, which can range from 0 to 53, with higher scores indicating better function. The change from baseline at 36 months was ‐5.63 ± 8.75 in the vitamin E group and ‐6.39 ± 8.99 in the placebo group. The sample sizes used to calculate these values were not reported. The difference was described as not statistically significant.
Number of participants experiencing one or more serious adverse events (SAE)
This was not reported in the study. There was no statistically significant difference between vitamin E and placebo groups in the rate of ten individual adverse events which were reported because they occurred in at least 5% of participants receiving donepezil or vitamin E and at least twice among participants receiving placebo.
Mortality
Five subjects died in each of the vitamin E (n = 257) and placebo (n = 259) groups during the double‐blind phase.
Other validated biomarkers
Not reported in the review.
Comparison 3: Vitamin E and C versus placebo
Only one study Naeini 2014 contributed to this comparison.
Primary outcomes
Incidence of all‐cause dementia
Not assessed.
Overall cognitive functioning
This was measured using the Iranian version of the MMSE (validated for the local population, range 0 to 30) after one year of treatment. The mean and standard error of the mean at six and 12 months were reported. The difference between the groups was described as not statistically significant at either time point.
We assumed that all participants described as completing the study were analysed and estimated the mean difference at the end of the study. This indicated that there may be no little or no effect of supplementation with vitamins E and C (MD 0.23, 95% CI ‐0.25 to 0.71; 1 study, 256 participants; Analysis 3.1).We considered this to be very low‐quality evidence, downgraded due to indirectness (inadequate definition of MCI), risk of bias, and imprecision (result from a single study).
Secondary outcomes
Mortality
There was one reported death, but the treatment allocation of this person was not reported.
None of our other secondary outcomes were reported.
Comparison 4: Chromium picolinate versus placebo
Only one study Krikorian 2010 contributed data to this comparison. This study was very small (n = 26). There were 15 participants in the intervention arm and 11 in the placebo arm.
Primary outcomes
The incidence of all‐cause dementia
Not assessed.
Overall cognitive functioning
Not assessed.
Secondary outcomes
Specific cognitive functioning subdomain: episodic memory
This was measured using the Californian Verbal Learning test (test for episodic verbal learning and memory) at 12 weeks. Group differences were not significant for performances on the CVLT learning trials (46.8 versus 45.8; P = 0.72), short‐delay recall (9.4 versus 8.4; P = 0.30), long‐delay recall (9.3 versus 9.5; P = 0.78), or recognition memory (14.4 versus 14.2; P = 0.77). We considered this to be very low‐quality evidence due to serious concern about study limitations and very serious concern about imprecision.
None of our other secondary outcomes were reported.
Discussion
Summary of main results
This review included eight RCTs which investigated the effect of vitamin or mineral supplements on the incidence of dementia or on cognitive function in participants with mild cognitive impairment at baseline. Five studies with 879 randomised participants investigated the effect of B vitamins; in four of these studies the intervention was a mixture of vitamins B12, B6 and folic acid and in one study it was folic acid only. The other supplements included were vitamin E (one study, 769 participants), vitamins E and C (one study, 256 participants) and chromium picolinate (one study, 26 participants).
None of the included studies assessed the incidence of all‐cause dementia, one of our primary outcomes. One study found that there was probably no effect of vitamin E on the probability of progression from MCI to dementia due to Alzheimer's disease over three years.
All of the studies reported on one or more measures of cognitive function.
For B vitamins, we found very low‐quality evidence on overall cognitive function. There was probably little or no effect on any of our specific cognitive subdomains of interest (episodic memory, executive functioning, and speed of processing). Only one study reported on each of global clinical impression and quality of life, and there was no evidence of any effect. There was only very low‐quality evidence on functional performance from one small, open‐label study. The very few data available on adverse events or mortality did not suggest any difference between groups. The only study reporting biomarker data found a reduction in the rate of brain atrophy over two years in the B vitamin group. We added to our protocol the reporting of subgroup data by baseline homocysteine (tHcy) level. The one study that reported such data found that there may be a significant benefit of B vitamins on episodic memory ‐ but not overall cognitive function or executive function ‐ of participants with tHcy above the median at baseline.
The study of vitamin E did not provide the data we needed to conduct analyses. The authors reported no significant effect of vitamin E supplementation on overall cognitive functioning, episodic memory, executive functioning, clinical global impression, functional performance, incidence of adverse events, or mortality.
The quality of evidence on vitamins E and C in combination (effect on overall cognitive function) and on chromium picolinate (effect on episodic memory) was very low so we had very little confidence in the results.
Overall completeness and applicability of evidence
The five trials all included community‐dwelling participants aged over 55 with mild cognitive impairment. In one of the studies of B vitamins, participants all had mild B12 deficiency at baseline at a level which is common in older people, but otherwise participants were not selected on the basis of nutritional status. Not all studies assessed nutritional status at baseline, but participants in all other studies had, or could be expected to have had, normal dietary intake for their population of origin and a low risk of specific vitamin or mineral deficiencies. The results of this review do not apply to people with significant nutritional deficiencies. In one study, participants had vascular cognitive impairment after a recent lacunar stroke; in the other studies, there was no selection for cause of cognitive impairment. Overall, the participants seemed to be quite well representative of people with MCI seen in clinical practice. The range of vitamin and mineral supplements tested was limited. Only B vitamins were investigated in more than one study and these studies all used different dose combinations so that it was not possible to isolate effects of individual B vitamins or to assess dose‐response relationships. The dose of folic acid used in some studies was similar to the maximum dietary intake in the UK population; doses of other vitamins were at least ten times more than the reference nutrient intake (see Appendix 3). All trials assessed different primary and secondary outcomes. Only one trial assessed progression to dementia due to Alzheimer's disease and none assessed progression to all‐cause dementia. Overall cognitive function was assessed mainly with the MMSE which has limited sensitivity to detect small changes in cognition in a population with MCI. There were few data on quality of life, global impression, functional performance, or adverse events. Only one study reported a biomarker outcome which has been widely used in MCI populations, namely, the rate of atrophy on structural MRI.
Quality of the evidence
There was some moderate‐quality evidence relating to the effect of B vitamins on specific cognitive domains and quality of life, and the effect of vitamin E on incidence of Alzheimer's dementia. The remaining evidence was of low‐ or very low‐quality. Some of the more serious concerns about risk of bias related to performance bias in one open‐label study, attrition bias in two studies and selective outcome reporting in two studies. For the comparisons of the vitamin E and C combination and chromium picolinate with placebo, the only evidence was of very low‐quality because of study limitations and very small sample sizes. The evidence concerning a possible differential effect on episodic memory in participants with higher or lower baseline homocysteine levels came from subgroups in a single study and must be regarded as preliminary.
Potential biases in the review process
We considered search biases to be unlikely. We used a standardised search strategy to identify articles, including unpublished studies. These search methods included a single‐concept search across multiple sources along with a search of the Cochrane trial register. This sensitive search approach may have identified studies that would have potentially been overlooked using less rigorous search methods. However, we found too few studies to conduct any formal tests to assess the likelihood of publication bias and this remains possible.
We selected only three specific cognitive subdomains as secondary outcomes. It is possible that effects on other specific cognitive subdomains could have been missed.
Where cognition is measured using several different instruments, it can be difficult to categorise instruments into specific cognitive subdomains and to make data pooling decisions. We tried to avoid bias by using a prespecified, hierarchical list of the most commonly used instruments, but it is possible that different categorisations could have led to different results.
Agreements and disagreements with other studies or reviews
We are not aware of other reviews of similar scope. The Collaboration of B‐vitamin Treatment Trialists have conducted a meta‐analysis of data on more than 22,000 older participants who were not selected for specific cognitive diagnoses (Clarke 2014). This review found no effect of B vitamins on overall or domain‐specific cognitive function despite lowering serum homocysteine levels by > 25%. Although not directly relevant to a population with mild cognitive impairment, this result does not support the hypotheses that B vitamin supplementation or homocysteine‐lowering are effective means to prevent cognitive decline.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 1 B vitamins versus placebo, outcome: 1.1 Overall cognitive function (MMSE).
Forest plot of comparison: 1 B vitamins versus placebo, outcome: 1.2 Episodic memory.
Forest plot of comparison: 1 B vitamins versus placebo, outcome: 1.3 Executive function.
Forest plot of comparison: 1 B vitamins versus placebo, outcome: 1.4 Speed of processing.
Comparison 1 B vitamins versus placebo, Outcome 1 Overall cognitive function (MMSE).
Comparison 1 B vitamins versus placebo, Outcome 2 Episodic memory.
Comparison 1 B vitamins versus placebo, Outcome 3 Executive function.
Comparison 1 B vitamins versus placebo, Outcome 4 Speed of processing.
Comparison 1 B vitamins versus placebo, Outcome 5 Quality of life (D‐QOL).
Comparison 1 B vitamins versus placebo, Outcome 6 Functional performance (ADL).
Comparison 3 Vitamins E and C versus placebo, Outcome 1 Overall cognitive function (MMSE).
| B vitamins compared to placebo for MCI | |||||
| Patient or population: MCI | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with B vitamins | ||||
| Incidence of dementia ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Overall cognitive function | MD with B vitamins was 0.44 MMSE points higher | 488 | ⊕⊝⊝⊝ | Due to the very low‐quality of the evidence, we cannot be sure of any effect of B vitamins on overall cognitive function. * 2 studies reported final score; 1 study reported change from baseline. From the 2 studies (n=150) which reported final scores, the mean MMSE with placebo was 26.97 points. | |
| Episodic memory | SMD with B vitamins was 0.09 higher | 397 | ⊕⊕⊕⊝ | B vitamins probably resulted in little to no difference in episodic memory. | |
| Executive function | SMD with B vitamins was 0.03 higher | 392 | ⊕⊕⊕⊝ | B vitamins probably resulted in little to no difference in executive function. | |
| Speed of processing | SMD with B vitamins was 0.04 higher | 173 | ⊕⊕⊕⊝ | B vitamins probably resulted in little to no difference in speed of processing. | |
| Quality of life | The mean quality of life was 3.5 points | MD 0 points | 138 | ⊕⊕⊕⊝ | B vitamins probably resulted in little to no difference in quality of life. |
| Mortality ‐ not reported | Reported by only one study (2/133 died in vitamin B group, 0/133 died in placebo group). | ‐ | ‐ | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded due to risk of bias. One study was at high risk of performance bias and at unclear risk of selection and detection bias. 2 Downgraded due to inconsistency. I2 = 87%. 3 Downgraded due to imprecision. 95% CI included little or no effect and small benefit of B vitamins. 4 Downgraded due to imprecision. 95% CI included small effects in either direction. 5 Downgraded due to imprecision. Result derived from one small study. aEpisodic memory assessed with Hopkins Verbal Learning Test, word learning and the Auditory Verbal Learning Test. bExecutive function assessed with CLOX, the Stroop test, and the Frontal Assessment Battery. cSpeed of processing assessed with Trail‐making Test A, digit cancellation, and the Digit‐Symbol Substitution Test. CLOX: Clock drawing executive test | |||||
| Vitamin E compared to placebo for MCI | |||
| Patient or population: MCI | |||
| Outcomes | Impact | № of participants | Certainty of the evidence |
| Incidence of dementia due to Alzheimer's disease | 76 cases in vitamin E group and 73 cases in placebo group (HR 1.02, 95% CI 0.74 to 1.41) | 516 | ⊕⊕⊕⊝ |
| Overall cognitive functioning | Single study reported no significant difference between groups in changes from baseline of MMSE or ADAS‐cog. Sample sizes not reported. | (1 RCT) | ⊕⊕⊝⊝ |
| Episodic memory | Single study reported no significant difference between groups. Sample size not reported. | (1 RCT) | ⊕⊕⊝⊝ |
| Executive functioning | Single study reported no significant difference between groups. Sample size not reported. | (1 RCT) | ⊕⊕⊝⊝ |
| Quality of life ‐ not measured | ‐ | ‐ | |
| Mortality | No significant difference in deaths reported between vitamin E, donepezil, and placebo groups during double‐blind phase of trial. | (1 RCT) | ‐ |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||
| GRADE Working Group grades of evidence | |||
| 1 Downgraded due to imprecision. 95% CI around hazard ratio included possible effect in both directions. 2 Downgraded due to imprecision. Single study. Sample size for this outcome not reported. 3 Downgraded due to risk of bias. High risk of bias due to incomplete outcome data and selective reporting. aEpisodic memory assessed using standardised composite z‐score incorporating ADAS immediate and delayed word‐recall scores and the New York University immediate and delayed paragraph‐recall scores. bExecutive function assessed using standardised composite z‐score incorporating the digits‐backward test, Symbol Digit Modalities Test, and number‐cancellation test. ADAS‐cog: Alzheimer's Disease Assessment Scale ‐ cognitive | |||
| Vitamin E + vitamin C compared to placebo for MCI | |||||
| Patient or population: MCI | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with vitamin E + vitamin C | ||||
| Incidence of dementia ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Overall cognitive function | The mean overall cognitive function was 26.6 points | MD 0.23 points higher | 256 | ⊕⊝⊝⊝ | Due to very low‐quality evidence, we cannot be sure of any effect of vitamin C + vitamin E on overall cognitive function. |
| Episodic memory ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Executive function ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Speed of processing ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Quality of life ‐ not measured | ‐ | ‐ | ‐ | ‐ | |
| Mortality ‐ not reported | ‐ | ‐ | ‐ | ‐ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded due to risk of bias. Unclear risks of selection, performance, and attrition bias. 2 Downgraded due to indirectness. Inadequate definition of MCI. 3 Downgraded due to imprecision. Result from a single small study. MCI: Mild cognitive impairment | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall cognitive function (MMSE) Show forest plot | 3 | 488 | Mean Difference (IV, Random, 95% CI) | 0.44 [‐0.23, 1.12] |
| 2 Episodic memory Show forest plot | 3 | 397 | Std. Mean Difference (IV, Random, 95% CI) | 0.09 [‐0.10, 0.29] |
| 3 Executive function Show forest plot | 3 | 392 | Std. Mean Difference (IV, Random, 95% CI) | 0.03 [‐0.23, 0.29] |
| 4 Speed of processing Show forest plot | 2 | 173 | Std. Mean Difference (IV, Random, 95% CI) | 0.04 [‐0.26, 0.34] |
| 5 Quality of life (D‐QOL) Show forest plot | 1 | 138 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐0.10, 0.10] |
| 6 Functional performance (ADL) Show forest plot | 1 | 75 | Mean Difference (IV, Random, 95% CI) | ‐0.78 [‐1.35, ‐0.21] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall cognitive function (MMSE) Show forest plot | 1 | 256 | Mean Difference (IV, Fixed, 95% CI) | 0.23 [‐0.25, 0.71] |
