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000164570 041__ $$aEnglish
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000164570 1001_ $$00000-0002-1399-6631$$aAli, Muhammad$$b0
000164570 245__ $$aLeveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
000164570 260__ $$aSan Francisco, California, US$$bPLOS$$c2022
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000164570 520__ $$aTwo 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.
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000164570 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000164570 650_7 $$2NLM Chemicals$$aApolipoprotein E4
000164570 650_7 $$2NLM Chemicals$$aBiomarkers
000164570 650_7 $$2NLM Chemicals$$aPeptide Fragments
000164570 650_7 $$2NLM Chemicals$$atau Proteins
000164570 650_2 $$2MeSH$$aAged
000164570 650_2 $$2MeSH$$aAged, 80 and over
000164570 650_2 $$2MeSH$$aAlzheimer Disease: cerebrospinal fluid
000164570 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000164570 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000164570 650_2 $$2MeSH$$aAmyloidosis
000164570 650_2 $$2MeSH$$aApolipoprotein E4: genetics
000164570 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000164570 650_2 $$2MeSH$$aDisease Susceptibility
000164570 650_2 $$2MeSH$$aEndophenotypes
000164570 650_2 $$2MeSH$$aHumans
000164570 650_2 $$2MeSH$$aMiddle Aged
000164570 650_2 $$2MeSH$$aPeptide Fragments: genetics
000164570 650_2 $$2MeSH$$aPositron-Emission Tomography
000164570 650_2 $$2MeSH$$atau Proteins: cerebrospinal fluid
000164570 650_2 $$2MeSH$$atau Proteins: genetics
000164570 693__ $$0EXP:(DE-2719)DIAN-20090101$$5EXP:(DE-2719)DIAN-20090101$$eLongitudinal Study on Dominantly Inherited Alzheimer's Disease$$x0
000164570 7001_ $$00000-0002-8021-4070$$aSung, Yun Ju$$b1
000164570 7001_ $$00000-0002-7677-5406$$aWang, Fengxian$$b2
000164570 7001_ $$aFernández, Maria V$$b3
000164570 7001_ $$aMorris, John C$$b4
000164570 7001_ $$aFagan, Anne M$$b5
000164570 7001_ $$aBlennow, Kaj$$b6
000164570 7001_ $$aZetterberg, Henrik$$b7
000164570 7001_ $$00000-0002-7290-6405$$aHeslegrave, Amanda$$b8
000164570 7001_ $$00000-0003-0073-7654$$aJohansson, Per M$$b9
000164570 7001_ $$00000-0002-4487-6405$$aSvensson, Johan$$b10
000164570 7001_ $$aNellgård, Bengt$$b11
000164570 7001_ $$aLleó, Alberto$$b12
000164570 7001_ $$00000-0002-3819-3245$$aAlcolea, Daniel$$b13
000164570 7001_ $$aClarimon, Jordi$$b14
000164570 7001_ $$aRami, Lorena$$b15
000164570 7001_ $$aMolinuevo, José Luis$$b16
000164570 7001_ $$0P:(DE-2719)2811727$$aSuárez-Calvet, Marc$$b17$$udzne
000164570 7001_ $$0P:(DE-2719)2812759$$aMorenas Rodriguez, Estrella$$b18$$udzne
000164570 7001_ $$0P:(DE-2719)9000907$$aKleinberger, Gernot$$b19$$udzne
000164570 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b20$$udzne
000164570 7001_ $$0P:(DE-2719)9000543$$aEwers, Michael$$b21$$udzne
000164570 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b22$$udzne
000164570 7001_ $$aFarlow, Martin R$$b23
000164570 7001_ $$00000-0002-3443-7716$$aPerrin, Richard J$$b24
000164570 7001_ $$aInitiative, Alzheimer’s Disease Neuroimaging$$b25$$eCollaboration Author
000164570 7001_ $$aNetwork, Dominantly Inherited Alzheimer$$b26$$eCollaboration Author
000164570 7001_ $$00000-0002-0276-2899$$aCruchaga, Carlos$$b27
000164570 773__ $$0PERI:(DE-600)2267670-3$$a10.1371/journal.pone.0267298$$gVol. 17, no. 5, p. e0267298 -$$n5$$pe0267298$$tPLOS ONE$$v17$$x1932-6203$$y2022
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