The three new pathways leading to Alzheimer's disease.

Genome-wide association studies (GWAS) promise a significant impact on the understanding of late-onset Alzheimer's disease (LOAD) as the genetic components have been estimated to account for 60-80% of the disease. The recent publication of results from large GWAS suggests that LOAD is now one of the best-understood complex disorders. Four recent large LOAD GWAS have resulted in the identification of nine novel loci. These genes are CLU--clusterin, PICALM--phosphatidylinositol-binding clathrin assembly protein, CR1--complement receptor 1, BIN1--bridging integrator 1, ABCA7--ATP-binding cassette transporter, MS4A cluster--membrane-spanning 4-domains subfamily A, CD2AP--CD2-associated protein, CD33--sialic acid-binding immunoglobulin-like lectin and EPHA1--ephrin receptor A1. Collectively, these genes now explain around 50% of LOAD genetics and map on to three new pathways linked to immune system function, cholesterol metabolism and synaptic cell membrane processes. These three new pathways are not strongly linked to the amyloid hypothesis that has driven so much recent thinking and open up avenues for intensive research with regard to the potential for therapeutic intervention.