A recent study of multivitamin use and memory in older adults is getting a lot of press and definitely needs to be put into perspective. Let’s begin with a quick review of the literature so far.
The clinical question is whether or not vitamin supplementation can improve memory or decrease the decline in memory as we age. Obviously there are a lot of subquestions here – if so, in which subpopulations, supplementing with which vitamins, and at what dose? There are also many possible outcomes to measure – attention, immediate recall, long term recall, verbal performance, and prevention of a diagnosis of dementia. There is an incredible amount of permutations. However, we can start with the most basic question and then try to drill down from there – is there any cognitive benefit to taking a multivitamin (MVM) in the general population or the general older population?
This question is actually hard to answer in the literature, as there are many study differences, overall study quality is generally low, and the findings are mixed. This 2021 systematic review specifically looked at B-vitamins and cognitive decline. B-vitamins are of special interest because they can decrease a metabolic product in the blood known as homocysteine. High levels of homocysteine are linked to poor vascular health and can increase the risk of blood clots and contribute to dementia and cognitive decline. The review found that B-vitamins specifically can delay cognitive decline in older adults, but larger and more rigorous clinical trials are needed to confirm this benefit.
Of note, a 2016 review looking specifically at different trials of B-vitamins in dementia found:
Most homocysteine-lowering trials with folate and vitamins B6 and/or B12 tested as protective agents against cognitive decline were poorly designed by including subjects unlikely to benefit during the trial period. In contrast, trials in high-risk subjects, which have taken into account the baseline B vitamin status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are consistent with modification of the Alzheimer’s disease process.
In other words, the protective effect of B-vitamins may only occur in those with baseline low B-vitamin levels and/or high homocysteine levels.
Other systematic reviews of MVM use in the general population find either no benefit or limited benefit. For example, the linked review found small benefit for immediate recall only, with no benefit for delayed recall or other cognitive functions measured. And also, the reviews generally conclude that the existing data is insufficient to adequately address the question. So there is definitively room for a larger and more rigorous study, and that is exactly the hole the current study seeks to fill.
The researchers in the current study actually had four treatment groups – cocoa extract plus placebo, MVM plus placebo, cocoa extract plus MVM, and just placebo. There were 2,262 subjects total enrolled in the study and evenly divided among the four groups. This was a three-year study, and so is larger and longer than other studies of MVM use and cognition. The assessment of the subjects was done over the phone, which is actually fine as the various cognitive exams can be done entirely verbally.
They found that all groups improved on all measures over the three years. This was expected and is due to the practice effect – subjects get better at the cognitive tasks with practice. They also generally plateaued between year 2 and 3 – also an expected pattern with the practice effect. So comparisons to baseline were essentially meaningless. All that mattered was comparison to placebo. There was a pretty high drop out rate:
Of enrolled participants, 2082 (92%) completed the cognitive assessment at Year 1, 1906 (84%) at Year 2, 1790 (79%) at Year 3, and 1732 (77%) in all 3 years of follow-up.
It’s hard to know the effects of this on the outcome, but such high dropout rates are a problem. That aside, the results showed a benefit for cognitive performance in the MVM vs placebo. There was no benefit for the cocoa extract vs placebo, and no addition benefit for adding cocoa extract to MVM. However, the authors also did a pre-planned subgroup analysis, looking at subject with baseline cardiovascular disease (CVD) and without. Those with CVD had a greater benefit from MVM use, and were the only subgroup that had a cognitive decline in the placebo group (as I stated, all other groups improved throughout the study). There was still a benefit for the non-CVD group, however, just not as dramatic.
For me, there is one glaring omission in this study – they did not evaluate baseline vitamin level or homocysteine levels. It is therefore possible that the entire effect seen in this study comes from the effect of B-vitamins on lowering homocysteine levels, which is consistent with the fact that the group who seemed to benefit the most from MVM use had baseline CVD. Also, I just want to emphasize that CVD is a major risk factor for dementia and cognitive decline.
This may all seem pedantic, but messaging to the public is critical. First, there is no evidence that MVM use improved cognition, as many mainstream outlets are reporting. It is far more likely, as the authors acknowledge, that MVM use simply decreased the decline in cognition in this older population. Therefore young healthy people should not expect any cognitive benefit to MVM use.
Further, it seems likely that the observed benefit here may be due to simply treating low B-vitamin and/or high homocysteine levels in this population, something which is already fairly well established. It is far better for people to have regular medical care in this age group, which includes measuring vitamin and metabolic levels and targeted supplementation, with monitoring, when appropriate. We would like to know, for example, which vitamins levels in particular are low. Also, not everyone responds to oral B12 supplementation and may require B12 injections. Thinking that a daily MVM will have you covered, therefore, may be counterproductive.
Also, this study only looked at cognition. Large reviews of hundreds of thousands of subjects have found not only is there no benefit to routine MVM use, some vitamins (like vitamin E) may be harmful in high doses. Routine MVM use, therefore, appears to be a harmful strategy, wasting money for most people and potentially resulting in excess supplementation with harmful effects. The proper messaging, in my opinion, is that older patients should be getting regular health visits, part of which will include monitoring nutritional factors which may lead to targeted evidence-based supplementation.
