SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease

Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent repl...

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Veröffentlicht in:	Human molecular genetics 2014-12, Vol.23 (24), p.6644-6658
Hauptverfasser:	Ramirez, Alfredo, van der Flier, Wiesje M, Herold, Christine, Ramonet, David, Heilmann, Stefanie, Lewczuk, Piotr, Popp, Julius, Lacour, André, Drichel, Dmitriy, Louwersheimer, Eva, Kummer, Markus P, Cruchaga, Carlos, Hoffmann, Per, Teunissen, Charlotte, Holstege, Henne, Kornhuber, Johannes, Peters, Oliver, Naj, Adam C, Chouraki, Vincent, Bellenguez, Céline, Gerrish, Amy, Heun, Reiner, Frölich, Lutz, Hüll, Michael, Buscemi, Lara, Herms, Stefan, Kölsch, Heike, Scheltens, Philip, Breteler, Monique M, Rüther, Eckart, Wiltfang, Jens, Goate, Alison, Jessen, Frank, Maier, Wolfgang, Heneka, Michael T, Becker, Tim, Nöthen, Markus M
Format:	Artikel
Sprache:	eng
Schlagworte:	Aged Alzheimer Disease - cerebrospinal fluid Alzheimer Disease - genetics Alzheimer Disease - pathology Amyloid beta-Peptides - cerebrospinal fluid Amyloid beta-Peptides - genetics Apolipoprotein E4 - cerebrospinal fluid Apolipoprotein E4 - genetics Association Studies Cognition Female Gene Expression Regulation Genome-Wide Association Study Humans Male Nuclear Proteins - cerebrospinal fluid Nuclear Proteins - genetics Peptide Fragments - cerebrospinal fluid Peptide Fragments - genetics Phosphorylation Polymorphism, Single Nucleotide RNA-Binding Proteins - cerebrospinal fluid RNA-Binding Proteins - genetics Serine-Arginine Splicing Factors Signal Transduction tau Proteins - cerebrospinal fluid tau Proteins - genetics
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Zusammenfassung:	Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aβ1-42.
ISSN:	0964-6906 1460-2083
DOI:	10.1093/hmg/ddu372