Urolithins from Walnuts Are Associated with Cognitive Performance: Ancillary Results from the Walnuts and Healthy Aging (WAHA) Randomized Trial.

Urolithins, microbiota-derived metabolites of ellagitannins, phenolic compounds abundant in walnuts, possess anti-inflammatory and antioxidant properties that might mitigate neuronal damage. However, clinical data supporting their effects on cognition are limited. In participants in the Walnuts and Healthy Aging (WAHA) trial, we determined urinary urolithin concentrations and examined their association with cognitive performance. The WAHA study was a parallel-group, 2-center (Barcelona, Spain; Loma Linda, California), randomized controlled trial. Cognitively healthy individuals followed a 2-year walnut-rich diet (15% daily energy) or a control diet excluding walnuts. Baseline and 2-year determinations included urinary urolithins by liquid chromatography-mass spectrometry and a comprehensive neuropsychological battery. The primary outcome was the association between changes in a global cognition composite score and urinary urolithins as the exposure, assessed by multivariable-adjusted regression. Secondary outcomes included associations of urolithins with domain-specific changes in memory, language, perception, and frontal function. A total of 612 participants (66% women, mean age 69 y) were included in analyses. Urolithin A, urolithin C and their glucuronide forms were objective biomarkers of walnut consumption (area under the curve at receiver operator characteristic analysis, 0.83; 95% CI, 0.80-0.86, 0.78; 95% CI, 0.74-0.82, 0.81; 95% CI, 0.77-0.84, and 0.80; 95% CI, 0.76-0.83, respectively). In the WAHA cohort following the walnut diet, changes in urolithin A glucuronide (β = 0.014 [95% CI, 0.003-0.025] per 1-SD) and urolithin C (β = 0.017 [95% CI, 0.001-0.033] per 1-SD) were associated with concurrent changes of the global cognition score. Urinary urolithins, particularly UroA, UroC and their glucuronides, are reliable biomarkers of walnut consumption. Changes in urolithin levels after 2 years of daily walnut consumption disclosed a direct association with cognitive performance in cognitively healthy older individuals. These findings provide clinical evidence linking dietary (poly)phenols and cognitive health.