O2-02-02

(AD) has highlighted the amyloid hypothesis as a working model for AD causation. The common late-onset form of AD has complex inheritance and thus far the only robust genetic association remains that with APOE. Objectives: As the genes causing early onset AD, APP, PSEN1 and PSEN2, encode proteins that are in pathways modulating the metabolism of APP and beta amyloid, we sought to explore their interrelationships using gene-gene linkage interaction and analysis of the correlation of their expression in brain. In addition, we examined other genes encoding proteins known to be involved in the synthesis or degradation of beta amyloid. Methods: Linkage analyses were carried out on 451 sibling pairs affected with late onset AD. Gene-gene interactions were tested by including the ibd sharing at the second locus as a covariate. Expression correlations were calculated on Affymetrix microarray data generated from around 70 cortical, cerebellum and striatal samples in our own laboratory (GEO accession GSE3790) and available AD hippocampal data (GEO accession GSE1297). Results: The strongest correlation in expression was between PSEN1 and BACE1 which were significantly positively correlated in the cortical (r 0.836, p 10-7) and hippocampal AD datasets (r 0.914, p 10-7) and also significantly correlated in many other samples. We also detected significant positive correlations between BACE1 and APP, APH1A and APP, ECE1 and APP, ECE2 and APP and ECE1 and ECE2. Significant linkage interactions were observed between the following pairs of loci: BACE1/PSEN1 (p 0.002), BACE1/APP (p 0.02), ECE2/APP (p 0.005), ECE2/IDE (p 0.012) and APH1B/PSEN2 (p 0.016). Conclusions: These strong correlations could arise simply through expression of genes in the same cell type. However, the results may indicate that increased levels of APP are correlated with increased levels of components of the major gamma and beta secretase enzymes and that APP itself might be responsible for inducing their expression. The fact that several pairs of genes show correlations both in expression and linkage indicate that interactions between them may play an important role in the susceptibility to AD, thereby informing the direction of future genetic studies.