Ira Driscoll1,2,3, Yue Ma2, Catherine L Gallagher4,5, Sterling C Johnson1,2,4, Sanjay Asthana1,2,4, Bruce P Hermann1,2,5, Mark A Sager1,2, Kaj Blennow6,7, Henrik Zetterberg6,7,8,9, Cynthia M Carlsson1,2,4, Corinne D Engelman1,2,10, Dena B Dubal11, Ozioma C Okonkwo1,2,4. 1. Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA. 2. Wisconsin Alzheimer's Institute, Madison, WI, USA. 3. Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA. 4. Geriatric Research Education and Clinical Center, William S. Middleton VA Hospital, Madison, WI, USA. 5. Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. 6. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden. 7. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 8. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK. 9. UK Dementia Research Institute at UCL, London, UK. 10. Departments of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. 11. Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
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.
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.
Authors: Tenielle Porter; Samantha C Burnham; Lidija Milicic; Greg Savage; Paul Maruff; Yen Ying Lim; David Ames; Colin L Masters; Ralph N Martins; Stephanie Rainey-Smith; Christopher C Rowe; Olivier Salvado; David Groth; Giuseppe Verdile; Victor L Villemagne; Simon M Laws Journal: Neurobiol Aging Date: 2019-01-06 Impact factor: 4.673
Authors: Mary Revelas; Anbupalam Thalamuthu; Christopher Oldmeadow; Tiffany-Jane Evans; Nicola J Armstrong; John B Kwok; Henry Brodaty; Peter R Schofield; Rodney J Scott; Perminder S Sachdev; John R Attia; Karen A Mather Journal: Mech Ageing Dev Date: 2018-06-08 Impact factor: 5.432
Authors: Clarisse F de Vries; Roger T Staff; Sarah E Harris; Dorota Chapko; Daniel S Williams; Polina Reichert; Trevor Ahearn; Christopher J McNeil; Lawrence J Whalley; Alison D Murray Journal: Neurobiol Aging Date: 2017-03-07 Impact factor: 4.673
Authors: Claire M Erickson; Stephanie A Schultz; Jennifer M Oh; Burcu F Darst; Yue Ma; Derek Norton; Tobey Betthauser; Catherine L Gallagher; Cynthia M Carlsson; Barbara B Bendlin; Sanjay Asthana; Bruce P Hermann; Mark A Sager; Kaj Blennow; Henrik Zetterberg; Corinne D Engelman; Bradley T Christian; Sterling C Johnson; Dena B Dubal; Ozioma C Okonkwo Journal: Neurology Date: 2019-03-13 Impact factor: 11.800
Authors: Muhammad Ali; Yun Ju Sung; Fengxian Wang; Maria V Fernández; John C Morris; Anne M Fagan; Kaj Blennow; Henrik Zetterberg; Amanda Heslegrave; Per M Johansson; Johan Svensson; Bengt Nellgård; Alberto Lleó; Daniel Alcolea; Jordi Clarimon; Lorena Rami; José Luis Molinuevo; Marc Suárez-Calvet; Estrella Morenas-Rodríguez; Gernot Kleinberger; Christian Haass; Michael Ewers; Johannes Levin; Martin R Farlow; Richard J Perrin; Carlos Cruchaga Journal: PLoS One Date: 2022-05-26 Impact factor: 3.752
Authors: Shweta Gupta; Arturo J Moreno; Dan Wang; Julio Leon; Chen Chen; Oliver Hahn; Yan Poon; Kenneth Greenberg; Nathaniel David; Tony Wyss-Coray; Daniel Raftery; Daniel E L Promislow; Dena B Dubal Journal: J Neurosci Date: 2022-04-15 Impact factor: 6.167