Higher Klotho Levels Shield Aging Brains From Cognitive Decline Despite Atrophy

Klotho is a longevity-associated protein whose circulating levels decline with age and have previously been linked to better cognitive outcomes. Ventricle-brain volume ratio (VBR), a well-validated marker of cerebral atrophy, is known to track cognitive decline and Alzheimer's disease (AD) progression. However, whether klotho can modify—or buffer—the harmful cognitive effects of brain atrophy had not been directly tested in a clinical cohort.

This cross-sectional study drew from two established Wisconsin cohorts (Wisconsin Alzheimer's Disease Research Center and Wisconsin Registry for Alzheimer's Prevention), enrolling 308 middle-aged to older adults (mean age 61.3 years; 80% female; 74% with parental history of AD) who were cognitively unimpaired. Participants underwent neuropsychological testing, structural MRI, and blood draw. Serum soluble α-klotho was quantified via ELISA. Cognitive outcomes included composite z-scores for global cognition, executive function, delayed recall, and immediate learning. VBR was computed as total ventricular volume divided by total brain volume × 100.

Across the full sample, a significant VBR × klotho interaction emerged for global cognition (β = 0.35, P = .01) and executive function (β = 0.41, P = .01). Participants with higher klotho performed better on these domains even when they had greater brain atrophy—a pattern suggesting resilience rather than simply reduced atrophy. Delayed recall and immediate learning did not show significant interactions in the full sample.

Age-stratified analyses using a median split (≤61.6 vs. >61.6 years) revealed that the protective interaction was confined to the older group. In older adults, higher klotho buffered the adverse effect of atrophy on global cognition (β = 0.59, P = .01), executive function (β = 0.71, P = .01), and immediate learning (β = 0.59, P = .03). The younger subgroup showed no significant VBR × klotho interactions, implying that klotho's neuroprotective role becomes especially relevant as aging advances and atrophy accumulates.

These findings are clinically meaningful because they suggest klotho does not simply prevent structural brain loss but may help the brain maintain functional cognitive capacity despite ongoing atrophy. The age-specificity of the effect aligns with the known trajectory of klotho decline in later life and suggests a window of opportunity for klotho-based interventions in older populations. Importantly, the cohort was enriched for AD risk via parental history, making these results directly relevant to prevention strategies. Limitations include the cross-sectional design, predominantly female and White sample, and inability to establish causality.