Genetic variability in response to Aβ deposition influences Alzheimer’s risk

Abstract

Abstract Genetic analysis of late-onset Alzheimer’s disease risk has previously identified a network of largely microglial genes that form a transcriptional network. In transgenic mouse models of amyloid deposition we have previously shown that the expression of many of the mouse orthologs of these genes are co-ordinately up-regulated by amyloid deposition. Here we investigate whether systematic analysis of other members of this mouse amyloid-responsive network predicts other Alzheimer’s risk loci. This statistical comparison of the mouse amyloid-response network with Alzheimer’s disease genome-wide association studies identifies 5 other genetic risk loci for the disease ( OAS1, CXCL10, LAPTM5, ITGAM and LILRB4 ). This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer’s risk. One Sentence Summary Identification of 5 new risk loci for Alzheimer’s by statistical comparison of mouse Aβ microglial response with gene-based SNPs from human GWAS