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

Driscoll, I; Ma, Y; Gallagher, CL; Johnson, SC; Asthana, S; Hermann, BP; Sager, MA; ... Okonkwo, OC; + view all (2021) Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes. Journal of Alzheimer's Disease , 79 (3) pp. 1297-1305. 10.3233/JAD-200944. Green open access

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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.

Type: Article
Title: Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.3233/JAD-200944
Publisher version: https://doi.org/10.3233/JAD-200944
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, executive function, memory
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10120636
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