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Leveraging large mu...
Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
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Ali, Muhammad (author)
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Sung, Yun Ju (author)
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Wang, Fengxian (author)
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show more...
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Fernández, Maria V (author)
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Morris, John C (author)
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Fagan, Anne M (author)
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- Blennow, Kaj, 1958 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Zetterberg, Henrik, 1973 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap,Institute of Neuroscience and Physiology, Department of Clinical Neuroscience
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Heslegrave, Amanda (author)
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- Johansson, Per, 1966 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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- Svensson, Johan (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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- Nellgård, Bengt, 1956 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för anestesiologi och intensivvård,Institute of Clinical Sciences, Department of Anesthesiology and Intensive care
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Lleó, Alberto (author)
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Alcolea, Daniel (author)
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Clarimon, Jordi (author)
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Rami, Lorena (author)
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Molinuevo, José Luis (author)
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Suárez-Calvet, Marc (author)
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Morenas-Rodríguez, Estrella (author)
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Kleinberger, Gernot (author)
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Haass, Christian (author)
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Ewers, Michael (author)
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Levin, Johannes (author)
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Farlow, Martin R (author)
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Perrin, Richard J (author)
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Cruchaga, Carlos (author)
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(creator_code:org_t)
- 2022-05-26
- 2022
- English.
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:5
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https://doi.org/10.1...
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Abstract
Subject headings
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- Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 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 Aβ42 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 Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -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 ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Klinisk laboratoriemedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Clinical Laboratory Medicine (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Psykiatri (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Psychiatry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Keyword
- Aged
- Aged
- 80 and over
- Alzheimer Disease
- cerebrospinal fluid
- genetics
- Amyloid beta-Peptides
- metabolism
- Amyloidosis
- Apolipoprotein E4
- genetics
- Biomarkers
- cerebrospinal fluid
- Disease Susceptibility
- Endophenotypes
- Humans
- Middle Aged
- Peptide Fragments
- genetics
- Positron-Emission Tomography
- tau Proteins
- cerebrospinal fluid
- genetics
Publication and Content Type
- ref (subject category)
- art (subject category)
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PloS one
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- By the author/editor
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Ali, Muhammad
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Sung, Yun Ju
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Wang, Fengxian
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Fernández, Maria ...
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Morris, John C
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Fagan, Anne M
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show more...
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Blennow, Kaj, 19 ...
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Zetterberg, Henr ...
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Heslegrave, Aman ...
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Johansson, Per, ...
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Svensson, Johan
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Nellgård, Bengt, ...
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Lleó, Alberto
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Alcolea, Daniel
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Clarimon, Jordi
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Rami, Lorena
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Molinuevo, José ...
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Suárez-Calvet, M ...
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Morenas-Rodrígue ...
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Kleinberger, Ger ...
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Haass, Christian
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Ewers, Michael
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Levin, Johannes
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Farlow, Martin R
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Perrin, Richard ...
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Cruchaga, Carlos
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Clinical Laborat ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Psychiatry
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
- Articles in the publication
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PloS one
- By the university
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University of Gothenburg