Genetic variants in PSEN2 and correlation to CSF beta-amyloid42 levels in AD

Beta-amyloid 42 (A beta 42) 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 A beta 42 concentrations and to confirm association of apolipoprotein E (APOE) alleles E4/E4 genotype with lower CSF A beta 42. Haplotype analysis of PSEN2 and APOE genotyping were performed in 175 Alzheimer's disease patients, as defined by clinical diagnosis and A beta 42 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 A beta 42 concentrations (p = 0.021) and lower A beta 42 concentrations in haplotype 5 carriers (p < 0.001). APOE E4/E4 carriers had lower A beta 42 levels (p = 0.009). Additive regression analysis showed an association of A beta 42 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 A beta 42 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 A beta 42 might help to stratify patients and develop specific treatment strategies. (C) 2012 Elsevier Inc. All rights reserved