Influence of low frequency PSEN1 variants on familial Alzheimer's disease risk in Brazil.

About 30-70% of familial Alzheimer's disease (AD) cases are related to mutations in presenilin-1 gene (PSEN1). Although the role of mutations and common variants in AD had been extensively investigated, the contribution of rare or low frequency PSEN1 variants on AD risk remains unclear. In the current study, we performed a mutational screening of PSEN1 coding exons and flanking intronic sequences among 53 index cases with familial history of AD from Rio de Janeiro (Brazil). Two missense variants (rs63750592; rs17125721), one rare and a low frequency variant, and two intronic variants (rs3025786; rs165932) were identified. In silico tools were used to predict the functional impact of the variants, revealing no changes in protein functionality by exonic variants. Otherwise, all variants were predicted to alter splicing signals. Prediction results, together with previous reports, suggest a correlation between rs17125721 and AD. So, a subsequent case-control study to evaluate the role of rs1712572 on AD risk was performed in an additional sample of 120 AD sporadic cases and in 149 elderly healthy controls by TaqMan Genotyping Assay. Our data indicates a risk association for rs17125721 in familial AD cases (OR=6.0; IC95%=1.06-33.79; p=0.042). In addition, we tested the multiplicative interaction between allele ε4 of the apolipoprotein E (APOE) and rs17125721 and no statistical association was found. Taken together, our findings provide new insight about the genetic relevance of low frequency PSEN1 variants for familial AD development.