Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk
Por:
Ali M., Sung Y.J., Wang F., Fernández M.V., Morris J.C., Fagan A.M., Blennow K., Zetterberg H., Heslegrave A., Johansson P.M., Svensson J., Nellgård B., Lleó A., Alcolea D., Clarimon J., Rami L., Molinuevo J.L., Suárez-Calvet M., Morenas-Rodríguez E., Kleinberger G., Haass C., Ewers M., Levin J., Farlow M.R., Perrin R.J., Cruchaga C.
Publicada:
1 ene 2022
Resumen:
Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity andassociated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE e4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aß42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aß positivity; odds ratio [OR] = 0.67 [95% CI, 0.55–0.78], ß = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19–0.77], ß = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27–0.96], ß = -0.68, p = 0.04) in cognitively normal participants, 60–80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE e4 genotype background may modulate Aß and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD. Copyright: © 2022 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Filiaciones:
Ali M.:
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
Sung Y.J.:
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
Wang F.:
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
Fernández M.V.:
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
Morris J.C.:
Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Fagan A.M.:
Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Blennow K.:
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, the University of Gothenburg, Mölndal, Sweden
Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
Zetterberg H.:
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, the University of Gothenburg, Mölndal, Sweden
Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
UK Dementia Research Institute at UCL, London, United Kingdom
Heslegrave A.:
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
UK Dementia Research Institute at UCL, London, United Kingdom
Johansson P.M.:
Department of Internal Medicine, Institute of Medicine, The Sahlgrenska Academy, the University of Gothenburg, Göteborg, Sweden
Svensson J.:
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
UK Dementia Research Institute at UCL, London, United Kingdom
Department of Anesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, Mölndal, Sweden
Institute of Clinical Sciences, The Sahlgrenska Academy, the University of Gothenburg, Gothenburg, Sweden
Nellgård B.:
Department of Internal Medicine, Institute of Medicine, The Sahlgrenska Academy, the University of Gothenburg, Göteborg, Sweden
Lleó A.:
Neurology Department, Hospital de Sant Pau, Barcelona, Spain
Alcolea D.:
Neurology Department, Hospital de Sant Pau, Barcelona, Spain
Clarimon J.:
Neurology Department, Hospital de Sant Pau, Barcelona, Spain
Rami L.:
IDIBAPS, Alzheimer´s Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic, Barcelona, Spain
Molinuevo J.L.:
IDIBAPS, Alzheimer´s Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic, Barcelona, Spain
Alzheimer´s Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, Barcelona, Spain
BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
Suárez-Calvet M.:
BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Morenas-Rodríguez E.:
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Kleinberger G.:
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Haass C.:
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Ewers M.:
Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
Levin J.:
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
Farlow M.R.:
Indiana Alzheimer Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, United States
Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
Perrin R.J.:
Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
Cruchaga C.:
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
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