Presenilin enhancer 2 (Pen2) is a subunit of the gamma-secretase complex which cleaves amyloid precursor protein (APP) to generate amyloid beta (A beta). We performed a systematic screening of all Pen2 exons and introns using direct sequencing to assess its role in the risk of developing late onset Alzheimer's disease (LOAD). 947 subjects (LOAD: 467; Controls: 480) were recruited for this study. We obtained three polymorphisms: rs10402601, rs3817622, and rs2293688. Among these three polymorphisms, there was an interaction between rs3817622 and apolipoprotein E (APOE) genotypes (P=0.002). In the subjects with APOE 4 allele, there was a significant difference in the distribution of alleles (P = 0.003) and genotypes (P = 0.007) between LOAD and control groups. ORs [95% confidence interval (CI)] of allele A and T/A+A/A genotypes were respectively 4.720 (1.517-10.654) and 3.886 (1.381-10.932) with allele T and genotype T/T as a reference. Our results suggest that there is an association between rs3817622 and the development of LOAD in APOE epsilon 4 carriers within the northern Chinese population. It is possible allele A of the Pen2 gene increases the risk for LOAD. (c) 2007 Elsevier B.V. All rights reserved.