Background: The protein Klotho is involved in biological processes related to longevity, cardiovascular health, and cognition. Serum Klotho levels have been associated with better cognition in animal models; moreover, lower Klotho concentrations in cerebrospinal fluid from subjects with late-onset Alzheimer’s disease (LOAD) have been reported. Objective: Our study aimed to examine the possible relationship between Klotho plasma concentrations and cognitive status in the elderly. Methods: We evaluated plasma Klotho levels in a sample of 320 elderly patients admitted to a Memory Clinic. Four groups of subjects were enrolled, including cognitively intact individuals complaining about memory loss (controls) and patients affected by LOAD, mild cognitive impairment, or vascular dementia (VD). The sample was stratified by plasma Klotho tertiles. Results: Lower levels of plasma Klotho (1st tertile) were associated with older age, higher prevalence of VD, single/multiple lacunar infarcts and leukoaraiosis, coronary heart disease and stroke, and higher levels of creatinine, homocysteine, and high-sensitivity C-reactive protein. On multivariate logistic regression analysis, the risk of VD was 3- and 4-fold in subjects belonging to the 1st tertile (≤514.8 pg/mL, OR 3.54, 95% CI 1.05–11.93) and 2nd tertile (> 514.8, < 659.1 pg/mL, OR 4.28, 95% CI 1.30–14.06) compared to the 3rd tertile (≥659.1 pg/mL). A significantly increased VD risk was found for Klotho values < 680 pg/mL. Conclusion: In a sample of elderly individuals, we found a significant association between low plasma Klotho levels and VD, but not LOAD. This finding suggests that, although these 2 forms of dementia might overlap, some physiopathological mechanisms related to VD and LOAD remain distinct.

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI: Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390: 45–51.
Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y: Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 1998; 242: 626–630.
Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H, Nagai R, Kuro-o M, Nabeshima Y: Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 1998; 424: 6–10.
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T: Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444: 770–774.
Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M: Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281: 6120–6123.
Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y: Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 2004; 565: 143–147.
Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y: alpha-Klotho as a regulator of calcium homeostasis. Science 2007; 316: 1615–1618.
Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M: Suppression of aging in mice by the hormone Klotho. Science 2005; 309: 1829–1833.
Xiao NM, Zhang YM, Zheng Q, Gu J: Klotho is a serum factor related to human aging. Chin Med J (Engl) 2004; 117: 742–747.
Hu MC, Kuro-o M, Moe OW: Renal and extrarenal actions of Klotho. Semin Nephrol 2013; 33: 118–129.
Saito Y, Yamagishi T, Nakamura T, Ohyama Y, Aizawa H, Suga T, Matsumura Y, Masuda H, Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R: Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun 1998; 248: 324–329.
Nagai R, Saito Y, Ohyama Y, Aizawa H, Suga T, Nakamura T, Kurabayashi M, Kuroo M: Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell Mol Life Sci 2000; 57: 738–746.
Kitagawa M, Sugiyama H, Morinaga H, Inoue T, Takiue K, Ogawa A, Yamanari T, Kikumoto Y, Uchida HA, Kitamura S, Maeshima Y, Nakamura K, Ito H, Makino H: A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 2013; 8:e56695.
Keles N, Caliskan M, Dogan B, Keles NN, Kalcik M, Aksu F, Kostek O, Aung SM, Isbilen B, Oguz A: Low serum level of klotho is an early predictor of atherosclerosis. Tohoku J Exp Med 2015; 237: 17–23.
Navarro-González JF, Donate-Correa J, Muros de Fuentes M, Pérez-Hernández H, Martínez-Sanz R, Mora-Fernández C: Reduced Klotho is associated with the presence and severity of coronary artery disease. Heart 2014; 100: 34–40.
Moreno JA, Izquierdo MC, Sanchez-Niño MD, Suárez-Alvarez B, Lopez-Larrea C, Jakubowski A, Blanco J, Ramirez R, Selgas R, Ruiz-Ortega M, Egido J, Ortiz A, Sanz AB: The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. J Am Soc Nephrol 2011; 22: 1315–1325.
Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L: Life extension factor klotho enhances cognition. Cell Rep 2014; 7: 1065–1076.
Semba RD, Moghekar AR, Hu J, Sun K, Turner R, Ferrucci L, O’Brien R: Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci Lett 2014; 558: 37–40.
Shardell M, Semba RD, Rosano C, Kalyani RR, Bandinelli S, Chia CW, Ferrucci L: Plasma klotho and cognitive decline in older adults: findings from the InCHIANTI study. J Gerontol A Biol Sci Med Sci 2016; 71: 677–682.
Almeida OP, Morar B, Hankey GJ, Yeap BB, Golledge J, Jablensky A, Flicker L: Longevity Klotho gene polymorphism and the risk of dementia in older men. Maturitas 2017; 101: 1–5.
Mengel-From J, Soerensen M, Nygaard M, McGue M, Christensen K, Christiansen L: Genetic variants in KLOTHO associate with cognitive function in the oldest old group. J Gerontol A Biol Sci Med Sci 2016; 71: 1151–1159.
Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Ama-ducci L, Orgogozo JM, Brun A, Hofman A, et al: Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993; 43: 250–260.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–944.
Lawton MP, Brody EM: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9: 179–186.
Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B: Current concepts in mild cognitive impairment. Arch Neurol 2001; 58: 1985–1992.
Folstein MF, Folstein SE, McHugh PR: “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.
Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW: Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. JAMA 1963; 185: 914–919.
Sheikh JI, Yesavage JA: Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol 1986; 5: 165–173.
Zuliani G, Ranzini M, Guerra G, Rossi L, Munari MR, Zurlo A, Volpato S, Atti AR, Blè A, Fellin R: Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia. J Psychiatr Res 2007; 41: 686–693.
Tisato V, Rimondi E, Brombo G, Volpato S, Zurlo A, Zauli G, Secchiero P, Zuliani G: Serum soluble tumor necrosis factor-related apoptosis-inducing ligand levels in older subjects with dementia and mild cognitive impairment. Dement Geriatr Cogn Disord 2016; 41: 273–280.
Donate-Correa J, Martín-Núñez E, Mora-Fernández C, Muros-de-Fuentes M, Pérez-Delgado N, Navarro-González JF: Klotho in cardiovascular disease: current and future perspectives. World J Biol Chem 2015; 6: 351–357.
Launer LJ: Demonstrating the case that AD is a vascular disease: epidemiologic evidence. Ageing Res Rev 2002; 1: 61–77.
de la Torre JC: Alzheimer disease as a vascular disorder: nosological evidence. Stroke 2002; 33: 1152–1162.
de la Torre JC: Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol 2004; 3: 184–190.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.