Mediating role of klotho protein in the impact of alcohol consumption on cognitive impairment in older adults: A cross-sectional analysis of NHANES data

JOURNAL/agad/04.03/02274129-202607000-00001/figure1/v/2026-06-18T113019Z/r/image-tiff Objectives: In light of concerns about the link between alcohol consumption and cognitive decline, there is a gap in the literature regarding the role of the Klotho protein in connecting alcohol to dementia. This study aimed to investigate whether serum Klotho protein mediates and/or moderates the association between alcohol consumption and cognitive performance in a nationally representative sample of older U.S. adults from the National Health and Nutrition Examination Survey (NHANES). Methods: This study analyzed cross-sectional information from 1168 participants aged ≥ 60 years derived from the NHANES between 2011 and 2014. The data included demographic, behavioral, and health determinants; details on the occurrence and average daily intake of alcohol consumption; concentrations of serum soluble Klotho protein; and evaluations of cognitive function. We performed both mediation and moderation analyses. Mediation was tested using bootstrapping, and moderation was tested by including a Klotho × alcohol interaction term in weighted linear regression. Results: Compared with females, males not only reported a higher prevalence of alcohol consumption (93.95% vs . 80.56%) but also reported greater mean daily alcohol intake (23.86 ± 41.84 g/day vs . 12.19 ± 23.33 g/day). In contrast, females had higher baseline Klotho levels ( P = 0.012). Both age and alcohol consumption were negatively correlated with Klotho levels, whereas cognition was positively correlated with Klotho levels (all P < 0.05). Importantly, our moderation analysis revealed that the interaction term (KL × Alcohol) was significant (β = –0.89, P < 0.001), indicating that individuals with lower Klotho levels experience a more pronounced negative effect of alcohol on cognition. Furthermore, Klotho concentrations were directly associated with CERAD-WL scores (weighted β [SE] = 0.086 [0.030 to 0.142], P = 0.003), accounting for 10.1% of the linkage between alcohol intake and Klotho-mediated CERAD-WL. Conclusion: In this cross-sectional study, Klotho seemed to moderate the alcohol–cognition association in older adults, with sex differences and a stronger negative link between alcohol and cognition among those with lower Klotho levels.