Which supplements have randomized controlled trials showing benefit for cognitive decline or dementia?

1. Multivitamins: the clearest randomized signal, but with caveats

A large, long-term randomized factorial trial and its cognitive ancillary studies (COSMOS and COSMOS‑Web/COSMOS‑MIND) found that a daily MVM (Centrum Silver) produced improved memory and slowed cognitive aging compared with placebo over three years in older adults, with results pooled across clinic subcohorts and meta‑analyses within the COSMOS program reinforcing the finding ^{[1] [2] [3] [4]}. These are high‑quality RCT data involving thousands of participants, but investigators caution that the mechanism—whether one nutrient, corrected micronutrient deficiency, or a combination effect—is not established and further replication is required ^{[1] [2]}.

2. Ginkgo biloba: promising small trials, undone by a large definitive study

Smaller RCTs and meta‑analyses have reported short‑term cognitive benefits of standardized Ginkgo biloba extract EGb‑761 in cognitive impairment and dementia (often at 240 mg/day over ~22–26 weeks) ^{[5] [9]}. However, a very large randomized trial (the GEM study) enrolling about 3,000 older adults found no reduction in incident dementia with ginkgo versus placebo, and major reviews conclude there is no conclusive prevention effect—leaving a conflicted picture: signal in some trials and meta‑analyses but null in the largest study ^{[5] [6] [10] [9]}.

3. B‑vitamins and homocysteine lowering: many RCTs, inconsistent clinical benefit

Dozens of randomized, placebo‑controlled trials have tested B‑vitamin formulations (folate, B12, B6) in older adults—nearly 2,900 participants across multiple trials—but systematic reviews find mixed results: biochemical changes and imaging signals in some studies have not reliably translated into clinical cognitive improvement across heterogeneous trials and populations ^{[8] [11]}. The literature contains many RCTs, yet a consistent, clinically meaningful effect on dementia prevention or slowing has not been established ^[8].

4. Omega‑3s, cocoa/berry polyphenols and other nutraceuticals: biologic rationale, inconsistent RCT outcomes

Omega‑3 fatty acids (DHA/EPA) have plausible mechanisms and some smaller RCTs suggested potential benefit, but larger or longer trials in mild‑to‑moderate Alzheimer’s disease did not show cognitive improvement, and systematic reviews report mixed findings ^{[6] [10] [12]}. Trials of cocoa flavanols and berry extracts have produced isolated positive RCTs for aspects of cognition, but these are not yet definitive for dementia prevention and were often small or short‑term ^{[2] [12]}.

5. Antioxidants and vitamin D: limited or negative randomized evidence

High‑quality systematic reviews and Cochrane assessments conclude there is no convincing evidence that vitamin E prevents progression from mild cognitive impairment to dementia or improves cognition broadly, though one trial reported slower functional decline in Alzheimer’s disease patients (moderate‑quality evidence) ^[5]. Reviews report either no available RCTs for vitamin D specifically aimed at dementia prevention or inconsistent trial data, leaving vitamin D’s role unresolved ^{[6] [13]}.

6. How to read the trials: heterogeneity, population, duration, and endpoints matter

Across the literature, heterogeneity in supplement formulations, doses, baseline nutritional status of participants, cognitive endpoints, and trial duration makes synthesis difficult; some interventions show short‑term cognitive effects or subgroup signals, but large, long trials often fail to replicate early positive findings—illustrating why guideline bodies remain cautious ^{[7] [11] [8]}. The clearest randomized evidence to date supports MVM supplementation for modest cognitive benefit in older adults (COSMOS), while other supplements carry mixed, limited, or negative RCT evidence ^{[1] [2] [5] [6] [8]}.