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

Beta-amyloid 42 (Abeta42) 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 Abeta42 concentrations and to confirm association of apolipoprotein E (APOE) alleles E4/E4 genotype with lower CSF Abeta42. Haplotype analysis of PSEN2 and APOE genotyping were performed in 175 Alzheimer's disease patients, as defined by clinical diagnosis and Abeta42 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 Abeta42 concentrations (p = 0.021) and lower Abeta42 concentrations in haplotype 5 carriers (p < 0.001). APOE E4/E4 carriers had lower Abeta42 levels (p = 0.009). Additive regression analysis showed an association of Abeta42 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 Abeta42 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 Abeta42 might help to stratify patients and develop specific treatment strategies