[논문]Genetic variants beyond amyloid and tau associated with cognitive decline : A cohort study

Kim, Hang-Rai; Lee, Taeyeop; Choi, Jung Kyoon; Jeong, Yong; Weiner, Michael W; Aisen, Pau; Weiner, Michael; Aisen, Paul; Petersen, Ronald; Jack, Clifford R; Jagust, William; Trojanowki, John Q; Toga, Arthur W; Beckett, Laurel; Green, Robert C; Saykin, Andrew J; Morris, John; Shaw, Leslie M; Khachaturian, Zaven; Sorensen, Greg; Carrillo, Maria; Kuller, Lew; Raichle, Marc; Paul, Steven; Davies, Peter; Fillit, Howard; Hefti, Franz; Holtzman, David; Mesulam, M. Marce; Potter, William; Snyder, Peter; Logovinsky, Veronika; Green, Robert C; Montine, Tom; Petersen, Ronald; Aisen, Paul; Jimenez, Gustavo; Donohue, Michael; Gessert, Devon; Harless, Kelly; Salazar, Jennifer; Cabrera, Yuliana; Walter, Sarah; Hergesheimer, Lindsey; Beckett, Laurel; Harvey, Danielle; Donohue, Michael; Jack, Clifford R; Bernstein, Matthew; Fox, Nick; Thompson, Paul; Schuff, Norbert; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Ka

doi:10.1212/wnl.0000000000010724

[해외논문] Genetic variants beyond amyloid and tau associated with cognitive decline : A cohort study 원문보기

Neurology, v.95 no.17, 2020년, pp. -

Kim, Hang-Rai (From the Graduate School of Medical Science & Engineering (H.-R.K., T.L., Y.J.), KAIST Institute for Health Science and Technology (H.-R.K., Y.J.), and Department of Bio and Brain Engineering (J.K.C., Y.J.), KAIST, Daejeon, Republic of Korea.) , Lee, Taeyeop (From the Graduate School of Medical Science & Engineering (H.-R.K., T.L., Y.J.), KAIST Institute for Health Science and Technology (H.-R.K., Y.J.), and Department of Bio and Brain Engineering (J.K.C., Y.J.), KAIST, Daejeon, Republic of Korea.) , Choi, Jung Kyoon (From the Graduate School of Medical Science & Engineering (H.-R.K., T.L., Y.J.), KAIST Institute for Health Science and Technology (H.-R.K., Y.J.), and Department of Bio and Brain Engineering (J.K.C., Y.J.), KAIST, Daejeon, Republic of Korea.) , Jeong, Yong (From the Graduate School of Medical Science & Engineering (H.-R.K., T.L., Y.J.), KAIST Institute for Health Science and Technology (H.-R.K., Y.J.), and Department of Bio and Brain Engineering (J.K.C., Y.J.), KAIST, Daejeon, Republic of Korea.) , Weiner, Michael W , Aisen, Pau , Weiner, Michael , Aisen, Paul , Petersen, Ronald , Jack, Clifford R , Jagust, William , Trojanowki, John Q , Toga, Arthur W , Beckett, Laurel , Green, Robert C , Saykin, Andrew J , Morris, John , Shaw, Leslie M , Khachaturian, Zaven , Sorensen, Greg , Carrillo, Maria , Kuller, Lew , Raichle, Marc , Paul, Steven , Davies, Peter , Fillit, Howard , Hefti, Franz , Holtzman, David , Mesulam, M. Marce , Potter, William , Snyder, Peter , Logovinsky, Veronika , Green, Robert C , Montine, Tom , Petersen, Ronald , Aisen, Paul , Jimenez, Gustavo , Donohue, Michael , Gessert, Devon , Harless, Kelly , Salazar, Jennifer , Cabrera, Yuliana , Walter, Sarah , Hergesheimer, Lindsey , Beckett, Laurel , Harvey, Danielle , Donohue, Michael , Jack, Clifford R , Bernstein, Matthew , Fox, Nick , Thompson, Paul , Schuff, Norbert , Borowski, Bret , Gunter, Jeff , Senjem, Matt , Vemuri, Prashanthi , Jones, David , Ka

Abstract ▼ AI-Helper

ObjectiveTo identify single nucleotide polymorphisms (SNPs) associated with cognitive decline independent of β-amyloid (Aβ) and tau pathology in Alzheimer disease (AD).MethodsDiscovery and replication datasets consisting of 414 individuals (94 cognitively normal control [CN], 185 with mild cognitive impairment [MCI], and 135 with AD) and 72 individuals (22 CN, 39 with MCI, and 11 with AD), respectively, were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Genome-wide association analysis was conducted to identify SNPs associated with individual cognitive function (measured with the Mini-Mental State Examination and Alzheimer's Disease Assessment Scale-Cognitive Subscale ) while controlling for the level of Aβ and tau (measured as CSF phosphorylated-tau/Aβ1-42). Gene ontology analysis was performed on SNP-associated genes.ResultsWe identified 1 significant (rs55906536, β = −1.91, standard error 0.34, p = 4.07 × 10−8) and 4 suggestive variants on chromosome 6 that were associated with poorer cognitive function. Congruent results were found in the replication data. A structural equation model showed that the identified SNP deteriorated cognitive function partially through cortical thinning of the brain in a region-specific manner. Furthermore, a bioinformatics analysis showed that the identified SNPs were associated with genes related to glutathione metabolism.ConclusionsIn this study, we identified SNPs related to cognitive decline in a manner that could not be explained by Aβ and tau levels. Our findings provide insight into the complexity of AD pathogenesis and support the growing literature on the role of glutathione in AD.

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