Serum Klotho Levels, Brain Structure, and Cognitive Performance

Importance: Ventricle-brain volume ratio (VBR), a marker of cerebral atrophy, is a robust correlate of cognition and a predictor of Alzheimer disease (AD) progression. Higher circulating concentrations of the longevity protein klotho have been linked to better cognition, but whether klotho modifies the known association between age-related brain atrophy and cognitive decline is unclear. Objective: To examine whether serum klotho moderates the association between VBR and cognition and whether this association differs in younger adults (age ≤61.6 years; median split) compared with older adults. Design, Setting, and Participants: This was a cross-sectional study using data from the Wisconsin Alzheimer Disease Research Center and the Wisconsin Registry for Alzheimer Prevention, collected from 2009 to 2023. This was a community-based, longitudinal study at a research center. Included in the analysis were middle-aged and older adults without cognitive impairment, most with a parental history of AD, who underwent neuropsychological testing, magnetic resonance image, and venipuncture. Exposure: Serum soluble α-klotho concentration, measured via enzyme-linked immunosorbent assay. Main Outcomes and Measures: Outcome measures included composite z scores for global cognition, executive function, delayed recall, and immediate learning. VBR was calculated as total ventricular volume divided by total brain volume ×100. Results: Across the entire sample (308 participants; mean [SD] age, 61.3 [6.5] years; 246 female [80%]; parental history of AD, 227 [74%]), the VBR × klotho interaction was significant, whereby those with higher serum klotho levels performed better on tests assessing global cognition (mean [SE], 0.35 [0.14]; 95% CI, 0.08-0.62; P = .01) and executive function (mean [SE], 0.41 [0.15]; 95% CI, 0.11-0.71; P = .01) but not delayed recall or immediate learning, despite having more brain atrophy. VBR × klotho interactions were not significant in the younger group. In the older group, the VBR × klotho interaction was significant, whereby those with higher circulating klotho levels performed better on tests of global cognition (mean [SE], 0.59 [0.24]; 95% CI, 0.12-1.06; P = .01), executive function (mean [SE], 0.71 [0.27]; 95% CI, 0.19-1.24; P = .01), and immediate learning (mean [SE], 0.59 [0.27]; 95% CI, 0.06-1.20; P = .03) but not delayed recall, despite having more brain atrophy. Conclusions and Relevance: Results suggest that circulating serum klotho levels modified the known adverse association between age-related brain atrophy and cognition in older, but not younger, adults at risk for AD, suggesting that the neuroprotective effects of klotho may be age dependent.