Effects of Nucleotide-Rich Kluyveromyces fragilis and Saccharomyces cerevisiae Yeast Extracts on Cognitive Function in Older Adults with Mild Cognitive Impairment: A Randomized Placebo-Controlled Trial

Background/Objectives: Mild cognitive impairment (MCI) may precede dementia, and safe nutritional strategies able to support cognitive function are of clinical interest. Dietary nucleotides may contribute to membrane phospholipid synthesis, synaptic function, and neuroprotective pathways; however, clinical evidence in older adults with MCI remains limited. This randomized placebo-controlled trial evaluated the efficacy and tolerability of nucleotide-rich yeast extracts from Kluyveromyces fragilis and Saccharomyces cerevisiae. Methods: Seventy-two participants (mean age 73.5 ± 7.7 years; range 60–85) were randomly assigned (1:1:1) to receive K. fragilis extract, S. cerevisiae extract, or placebo once daily for 180 days. Cognitive outcomes were assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) at baseline (T0), 90 days (T1), and 180 days (T2); quality of life was assessed using the SF-12 questionnaire at T0 and T2. Treatment effects were analyzed using linear mixed-effects models adjusted for age and sex. Results: After 180 days, MoCA scores increased by 4.42 points in the K. fragilis group and 3.92 points in the S. cerevisiae group, compared with 0.58 points in the placebo group (time × treatment p < 0.001; T0–T2 within-group p < 0.001 for both active groups and p = 0.14 for placebo). MMSE scores increased by 1.62 and 3.11 points in the K. fragilis and S. cerevisiae groups, respectively, compared with 0.25 points in the placebo group (time × treatment p < 0.001; T0–T2 within-group p < 0.001 for both active groups and p = 0.57 for placebo). The SF-12 mental component score increased by 7.50 and 9.16 points in the two active groups, respectively (time × treatment p = 0.022; T0–T2 p = 0.0013 and p < 0.001, respectively), while physical quality-of-life scores did not change significantly (PCS time × treatment p = 0.11). No adverse events were reported. Conclusions: Nucleotide-rich K. fragilis and S. cerevisiae yeast extracts were well tolerated and were associated with improved cognitive scores over six months in older adults with MCI. Larger multicenter trials are needed to confirm these findings.