Nutritional supplementation is increasingly regarded as a potential strategy to preserve or enhance cognitive function in individuals with healthy aging and mild cognitive impairment (MCI). However, its overall efficacy remains uncertain due to inconsistent findings across clinical trials.

In accordance with the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Network Meta-Analyses, we conducted a comprehensive systematic search. Our inclusion criteria focused on randomized controlled trials (RCTs) that examined the impact of nutrient supplementation on cognitive function within healthy aging and MCI patients. The primary outcome of interest was the change in cognitive function, while the secondary outcome involved alterations in blood biochemical markers (e.g., homocysteine, vitamin B12, and serum folate levels).

The meta-analysis results indicated that docosahexaenoic acid (DHA)+eicosapentaenoic acid (EPA)+vitamin E+tryptophan+melatonin, as well as melatonin alone, significantly enhanced global cognitive function. Additionally, DHA, folic acid+DHA, and the DHA+EPA+vitamin E+tryptophan+melatonin were all effective in augmenting memory. DHA alone was found to be beneficial in improving processing speed, whereas vitamin D3 was associated with improvements in visuospatial function. Notably, sensitivity analyses revealed that while most domain-specific effects remained stable, the rankings of certain small-sample interventions were sensitive to study duration and sample size. Supplementation with folic acid, vitamin B12, and vitamin B6, whether administered individually or in combination, resulted in varying improvements in blood biomarkers, including homocysteine, vitamin B12, and serum folate levels.

Nutritional supplementation demonstrates nuanced, domain-specific benefits rather than universal cognitive enhancement. While specific multi-nutrient combinations show potential, their effects are significantly influenced by baseline cognitive status, age, and intervention duration. Our findings suggest that nutritional strategies should be tailored to individual cognitive profiles, emphasizing the need for personalized interventions and further high-quality, longitudinal trials to confirm long-term clinical impact.