Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes¹

Article type: Research Article

Authors: Driscoll, Ira^{a; b; c; *} | Ma, Yue^b | Gallagher, Catherine L.^{d; e} | Johnson, Sterling C.^{a; b; d} | Asthana, Sanjay^{a; b; d} | Hermann, Bruce P.^{a; b; e} | Sager, Mark A.^{a; b} | Blennow, Kaj^{f; g} | Zetterberg, Henrik^{f; g; h; i} | Carlsson, Cynthia M.^{a; b; d} | Engelman, Corinne D.^{a; b; j} | Dubal, Dena B.^k | Okonkwo, Ozioma C.^{a; b; d}

Affiliations: [a] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA | [b] Wisconsin Alzheimer’s Institute, Madison, WI, USA | [c] Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA | [d] Geriatric Research Education and Clinical Center, William S. Middleton VA Hospital, Madison, WI, USA | [e] Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [f] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden | [g] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [h] Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK | [i] UK Dementia Research Institute at UCL, London, UK | [j] Departments of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [k] Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA

Correspondence: [*] Correspondence to: Ira Driscoll, PhD, and Ozioma Okonkwo, PhD, Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA. Tel.: +1 608 265 4479; E-mail: [email protected] and [email protected].

Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JAD-219006, available at https://content.iospress.com/articles/journal-of-alzheimers-disease/jad219006.

Abstract: Background:Identification of new genetic variants that modify Alzheimer’s disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. Objective:To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. Methods:Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET). Results:In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥ 0.14). Conclusion:Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, executive function, memory

DOI: 10.3233/JAD-200944

Journal: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1297-1305, 2021