Higher Klotho Levels May Protect Aging Brains
New evidence links a longevity protein to preserved thinking skills despite brain shrinkage in adults at risk for Alzheimer disease.
In adults at higher genetic risk for Alzheimer disease, higher blood levels of the longevity protein klotho were associated with better cognitive performance even when brain imaging showed more age-related atrophy, with the effect strongest in older individuals.
Study Details
Age-related brain atrophy is a well-known marker of cognitive decline and Alzheimer disease progression. One commonly used measure is the ventricle–brain volume ratio, which reflects how much the brain has shrunk relative to the fluid-filled spaces inside it. Separately, higher circulating levels of klotho, a protein linked to longevity and metabolic health, have been associated with better cognitive outcomes.
What has been unclear is whether klotho can actually modify the harmful relationship between brain atrophy and cognition. To address this, researchers analyzed data from middle-aged and older adults without cognitive impairment, most of whom had a parental history of Alzheimer disease.
Methodology
Researchers conducted a cross-sectional analysis of 308 cognitively unimpaired adults enrolled in long-running Alzheimer prevention cohorts in Wisconsin. Participants underwent brain MRI, blood testing, and detailed neuropsychological assessments.
Serum soluble α-klotho levels were measured using standardized laboratory assays. Brain atrophy was quantified using the ventricle–brain volume ratio. Cognitive outcomes were summarized using composite scores for global cognition, executive function, immediate learning, and delayed recall. Analyses also compared younger and older participants using a median age split.
Key Findings
Higher klotho levels weakened the negative link between brain atrophy and global cognition.
The same protective pattern was seen for executive function, a key skill for planning and decision-making.
In older adults, higher klotho was also linked to better immediate learning, despite greater brain atrophy.
These associations were not observed in younger participants, suggesting an age-dependent effect.
Delayed recall did not show a significant association with klotho levels.
Implications for Practice
For patients, these findings offer cautious optimism that biological resilience factors may help preserve thinking skills even as the brain ages structurally. Klotho does not appear to stop brain atrophy itself, but it may help the brain function better in spite of it.
For clinicians and researchers, the study strengthens interest in klotho as a potential therapeutic target or biomarker in aging and Alzheimer prevention. The age-specific effects also suggest that timing may matter, with later-life interventions possibly offering greater benefit. Importantly, these results are observational and do not support klotho supplementation outside of research settings, but they provide a strong rationale for future clinical trials.