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.
Czaplicki et al. (2026) studied this question.