4.5 Article

Circulating Klotho Is Higher in Cerebrospinal Fluid than Serum and Elevated Among KLOTHO Heterozygotes in a Cohort with Risk for Alzheimer's Disease

Journal

JOURNAL OF ALZHEIMERS DISEASE
Volume 90, Issue 4, Pages 1557-1569

Publisher

IOS PRESS
DOI: 10.3233/JAD-220571

Keywords

Alzheimer's disease; cerebrospinal fluid; KL-VS; Klotho; serum

Categories

Funding

  1. National Institute on Aging [R21 AG051858, R01 AG027161, P30 AG062715]
  2. National Institute of Neurological Disorders and Stroke [R01 NS092918]
  3. Clinical and Translational Science Award [UL1RR025011]
  4. Extendicare Foundation
  5. Alzheimer's Association
  6. Wisconsin Alumni Research Foundation
  7. Veterans Administration

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This study investigated the variation of Klotho concentrations and its association with Alzheimer's disease risk factors. The results showed that Klotho concentrations were higher in KL-VS carriers and in cerebrospinal fluid compared to serum. Females and younger individuals also had higher Klotho levels. These findings suggest that fluid source, KL-VS genotype, age, and sex should be taken into consideration when analyzing the effects of circulating Klotho on brain health.
Background: Klotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease. Objective: Test whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer's disease risk factors. Methods: Circulating klotho was measured in serum (n = 1,116) and CSF (n = 183) of cognitively intact participants (aged 62.4 +/- 6.5 years; 69.5% female). KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics. Results: Serum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF. Conclusion: In a cohort enriched for risk for Alzheimer's disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health.

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