Home > Publications Database > Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk. > print

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024 7 _ |a pmc:PMC9135221
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024 7 _ |a 10.1371/journal.pone.0267298
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041 _ _ |a English
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100 1 _ |a Ali, Muhammad
|0 0000-0002-1399-6631
|b 0
245 _ _ |a Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
260 _ _ |a San Francisco, California, US
|c 2022
|b PLOS
336 7 _ |a article
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336 7 _ |a ARTICLE
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520 _ _ |a 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.
536 _ _ |a 352 - Disease Mechanisms (POF4-352)
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650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 7 |a Apolipoprotein E4
|2 NLM Chemicals
650 _ 7 |a Biomarkers
|2 NLM Chemicals
650 _ 7 |a Peptide Fragments
|2 NLM Chemicals
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Aged, 80 and over
|2 MeSH
650 _ 2 |a Alzheimer Disease: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Amyloidosis
|2 MeSH
650 _ 2 |a Apolipoprotein E4: genetics
|2 MeSH
650 _ 2 |a Biomarkers: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Disease Susceptibility
|2 MeSH
650 _ 2 |a Endophenotypes
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Peptide Fragments: genetics
|2 MeSH
650 _ 2 |a Positron-Emission Tomography
|2 MeSH
650 _ 2 |a tau Proteins: cerebrospinal fluid
|2 MeSH
650 _ 2 |a tau Proteins: genetics
|2 MeSH
693 _ _ |0 EXP:(DE-2719)DIAN-20090101
|5 EXP:(DE-2719)DIAN-20090101
|e Longitudinal Study on Dominantly Inherited Alzheimer's Disease
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700 1 _ |a Sung, Yun Ju
|0 0000-0002-8021-4070
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700 1 _ |a Wang, Fengxian
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700 1 _ |a Fernández, Maria V
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700 1 _ |a Morris, John C
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700 1 _ |a Fagan, Anne M
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700 1 _ |a Blennow, Kaj
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700 1 _ |a Zetterberg, Henrik
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700 1 _ |a Heslegrave, Amanda
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700 1 _ |a Johansson, Per M
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700 1 _ |a Svensson, Johan
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700 1 _ |a Nellgård, Bengt
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700 1 _ |a Lleó, Alberto
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700 1 _ |a Alcolea, Daniel
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700 1 _ |a Clarimon, Jordi
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700 1 _ |a Rami, Lorena
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700 1 _ |a Molinuevo, José Luis
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700 1 _ |a Suárez-Calvet, Marc
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700 1 _ |a Morenas Rodriguez, Estrella
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700 1 _ |a Kleinberger, Gernot
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700 1 _ |a Haass, Christian
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700 1 _ |a Ewers, Michael
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700 1 _ |a Levin, Johannes
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700 1 _ |a Farlow, Martin R
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700 1 _ |a Perrin, Richard J
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700 1 _ |a Initiative, Alzheimer’s Disease Neuroimaging
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700 1 _ |a Network, Dominantly Inherited Alzheimer
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700 1 _ |a Cruchaga, Carlos
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773 _ _ |a 10.1371/journal.pone.0267298
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