Background: Optimal interventions to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia are uncertain.

Purpose: To summarize the evidence on efficacy and harms of over-the-counter (OTC) supplements to prevent or delay cognitive decline, MCI, or clinical Alzheimer-type dementia in adults with normal cognition or MCI but no dementia diagnosis.

Data sources: Multiple electronic databases from 2009 to July 2017 and bibliographies of systematic reviews.

Study selection: English-language trials of at least 6 months' duration that enrolled adults without dementia and compared cognitive outcomes with an OTC supplement versus placebo or active controls.

Data extraction: Extraction performed by a single reviewer and confirmed by a second reviewer; dual-reviewer assessment of risk of bias; consensus determination of strength of evidence.

Data synthesis: Thirty-eight trials with low to medium risk of bias compared ω-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C or β-carotene, multi-ingredient supplements, or other OTC interventions with placebo or other supplements. Few studies examined effects on clinical Alzheimer-type dementia or MCI, and those that did suggested no benefit. Daily folic acid plus vitamin B12 was associated with improvements in performance on some objectively measured memory tests that were statistically significant but of questionable clinical significance. Moderate-strength evidence showed that vitamin E had no benefit on cognition. Evidence about effects of ω-3 fatty acids, soy, ginkgo biloba, folic acid alone or with other B vitamins, β-carotene, vitamin C, vitamin D plus calcium, and multivitamins or multi-ingredient supplements was either insufficient or low-strength, suggesting that these supplements did not reduce risk for cognitive decline. Adverse events were rarely reported.

Limitation: Studies had high attrition and short follow-up and used a highly variable set of cognitive outcome measures.

Conclusion: Evidence is insufficient to recommend any OTC supplement for cognitive protection in adults with normal cognition or MCI.

Primary funding source: Agency for Healthcare Research and Quality.