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

Article type: Research Article

Authors: Gaitán, Julian M.^a | Asthana, Sanjay^{a; b; c} | Carlsson, Cynthia M.^{a; b; c} | Engelman, Corinne D.^{a; b; d} | Johnson, Sterling C.^{a; b; c} | Sager, Mark A.^{a; b} | Wang, Dan^e | Dubal, Dena B.^{e; 1; *} | Okonkwo, Ozioma C.^{a; b; c; 1; *}

Affiliations: [a] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [b] Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [c] Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA | [d] Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [e] Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, SanFrancisco, CA, USA

Correspondence: [*] Correspondence to:Dena B. Dubal, MD, PhD, University of California –San Francisco Weill Institute for Neurosciences, 675 Nelson Rising Lane, San Francisco, CA 94158, USA. Tel.: +1 415 502 7237; E-mail: [email protected] and Ozioma C. Okonkwo, PhD, University of Wisconsin— Madison, J5/156M, Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. Tel.: +1 608 265 4479; E-mail: [email protected].

Note: [1] Denotes co-senior authorship.

Abstract: 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.

Keywords: Alzheimer’s disease, cerebrospinal fluid, KL-VS, Klotho, serum

DOI: 10.3233/JAD-220571

Journal: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1557-1569, 2022