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Serum Klotho Levels, Brain Structure, and Cognitive Performance
Alec M Czaplicki1,2, Ira Frahmand Driscoll1,2, Yue Ma1,2
1Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison.
JAMA Neurology
|February 2, 2026
Summary
Higher klotho levels may protect cognition against brain atrophy in older adults at risk for Alzheimer disease (AD). This effect was not observed in younger adults, suggesting klotho
Area of Science:
- Neuroscience
- Gerontology
- Biochemistry
Background:
- Ventricle-brain volume ratio (VBR) indicates cerebral atrophy and predicts Alzheimer disease (AD) progression.
- Higher klotho concentrations are associated with better cognition, but its role in modifying the VBR-cognition link is unknown.
Purpose of the Study:
- To investigate if serum klotho moderates the association between VBR and cognition.
- To determine if this moderation differs between younger (≤61.6 years) and older adults.
Main Methods:
- Cross-sectional study (2009-2023) with data from the Wisconsin AD Research Center and Registry.
- Included 308 non-cognitively impaired middle-aged and older adults, most with a parental history of AD.
- Measured serum soluble α-klotho, VBR, and cognitive functions (global cognition, executive function, delayed recall, immediate learning).
Main Results:
- A significant VBR × klotho interaction was found across the entire sample: higher klotho correlated with better global cognition and executive function despite greater VBR.
- This interaction was not significant in younger adults.
- In older adults, higher klotho was associated with better global cognition, executive function, and immediate learning, even with increased VBR.
Conclusions:
- Serum klotho levels appear to modify the negative association between brain atrophy and cognition in older adults at risk for AD.
- The neuroprotective effects of klotho may be age-dependent, being more pronounced in older individuals.
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