title: Genetic variants in PSEN2 and correlation to CSF β-amyloid42 levels in AD.
abstract: Beta-amyloid 42 (Aβ42) concentrations in cerebrospinal fluid (CSF) are significantly decreased in Alzheimer's disease (AD). The aim of this study was to correlate genetic variability in presenilin 2 (PSEN2) in relation to Aβ42 concentrations and to confirm association of apolipoprotein E (APOE) alleles E4/E4 genotype with lower CSF Aβ42. Haplotype analysis of PSEN2 and APOE genotyping were performed in 175 Alzheimer's disease patients, as defined by clinical diagnosis and Aβ42 levels. One distinct haploblock in PSEN2 was detected and the frequent haplotypes were analyzed using 4 tagging single nucleotide polymorphisms (SNPs). We found an association between haplotype 2 and higher CSF Aβ42 concentrations (p = 0.021) and lower Aβ42 concentrations in haplotype 5 carriers (p < 0.001). APOE E4/E4 carriers had lower Aβ42 levels (p = 0.009). Additive regression analysis showed an association of Aβ42 level with APOE genotype (p = 0.024), haplotype 4 (p = 0.064), and haplotype 5 (p = 0.04), whereas gender, age at onset and Mini Mental State Examination (MMSE) remained insignificant. Using CSF Aβ42 as a biomarker we replicated genetic influences in APOE and observed a significant influence of a new haplotype in PSEN2. A better understanding of genetic influences on biomarkers like CSF Aβ42 might help to stratify patients and develop specific treatment strategies.
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Lebedeva
authors.forename: Julia C
authors.initials: JC
authors.lastname: Stingl
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Estifanos
authors.initials: E
authors.lastname: Ghebremedhin
authors.forename: Joachim
authors.initials: J
authors.lastname: Strauss
authors.forename: Esra
authors.initials: E
authors.lastname: Özer
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Björn
authors.initials: B
authors.lastname: von Einem
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Tumani
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Riepe
authors.forename: Josef
authors.initials: J
authors.lastname: Högel
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D020641:Polymorphism, Single Nucleotide; D053766:Presenilin-2 / Q000235:genetics*; D012044:Regression Analysis
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; C075222:amyloid beta-protein (1-42)