Clinician Article

Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life.

  • Rutjes AW
  • Denton DA
  • Di Nisio M
  • Chong LY
  • Abraham RP
  • Al-Assaf AS, et al.
Cochrane Database Syst Rev. 2018 Dec 17;12:CD011906. doi: 10.1002/14651858.CD011906.pub2. (Review)
PMID: 30556597
Read abstract Read evidence summary Read full text
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 5/7
  • Public Health
    Relevance - 6/7
    Newsworthiness - 4/7


BACKGROUND: Vitamins and minerals play multiple functions within the central nervous system which may help to maintain brain health and optimal cognitive functioning. Supplementation of the diet with various vitamins and minerals has been suggested as a means of maintaining cognitive function, or even of preventing dementia, in later life.

OBJECTIVES: To evaluate the effects of vitamin and mineral supplementation on cognitive function in cognitively healthy people aged 40 years or more.

SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov and the WHO Portal/ICTRP from inception to 26th January 2018.

SELECTION CRITERIA: We included randomised controlled trials that evaluated the cognitive effects on people aged 40 years or more of any vitamin or mineral supplements taken by mouth for at least three months.

DATA COLLECTION AND ANALYSIS: Study selection, data extraction, and quality assessments were done in duplicate. Vitamins were considered broadly in the categories of B vitamins, antioxidant vitamins, and combinations of both. Minerals were considered separately, where possible. If interventions and outcomes were considered sufficiently similar, then data were pooled. In order to separate short-term cognitive effects from possible longer-term effects on the trajectory of cognitive decline, data were pooled for various treatment durations from 3 months to 12 months and up to 10 years or more.

MAIN RESULTS: In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow-up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow-up > 5 years. Only two studies had participants whose mean age was < 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer-term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low.We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio- or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from -0.03 to 0.06) and may also have no effect at 5-10 years (SMD -0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia.We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß-carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low-certainty evidence of benefit associated with ß-carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low-certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E.One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low- to moderate-certainty evidence of no effect of vitamin D3 and calcium supplements at any time-point up to 10 years on overall cognitive function (MD after a mean of 7.8 years -0.1 MMSE points, 95% CI -0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months.We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate-certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI -0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate.From one study with 3711 participants, there was low-certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13).Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low-certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI -0.14 to 0.38).

AUTHORS' CONCLUSIONS: We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (< 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long-term supplementation with antioxidant vitamins. These may be the most promising for further research.

Clinical Comments

Family Medicine (FM)/General Practice (GP)

As a Family Physician, I'd expect these results. They are consistent with almost all large scale study results on benefit of nutritional supplements. There is a good concise summary of the evidence that's useful when counseling patients on vitamin/supplement use.

General Internal Medicine-Primary Care(US)

Massive complex cochrane review to elucidate the association of vitamins and supplements with cognitive function. As the authors state, unfortunately the study is hampered from the start, as most "participants were enrolled in studies which were not designed primarily to assess cognition, and "often had no baseline cognitive" assessment. Further breakdown into B vitamins, antioxidants, calcium and Vit D also failed to yield any association with a potential signal for B-carotene after 18 years of use. This analysis is important for the massive vitamin and supplement industry claims of benefit and patient discussion with their primary care provider. The study also begs for a cohort analysis with a sound baseline assessment and brief cognitive assessments at follow-up.

Public Health

This reinforces prior research and recommendations. While the supplements generally do no harm, they may be an added expense and may distract patients (and providers) from more important healthful behaviors such as exercise, smoking cessation or alcohol moderation.

Public Health

Could this be a possibly useful reference to discuss with/highlight to patients with concerns wanting more info?

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