Other genes implicated in Alzheimer's disease

Susceptibility to Alzheimer's Disease (AD) most likely results from many genetic and environmental risk factors and their interplay. Apolipoprotein E (APOE) and the nine novel genetic risk loci identified from the recent genome-wide association studies (GWAS) account for a portion of the estimated genetic susceptibility to AD [1]. While it is possible that discovery of the actual functional genetic risk polymorphisms at these novel loci will help explain a larger fraction of the AD risk, the more likely scenario is the existence of many more AD risk genes. Indeed, hundreds of genes have been implicated in risk of AD, since the early 1990s [2]. Although some of these are likely false positive findings due to underpowered studies, others have arisen from well-powered studies, were replicated by some follow-up efforts and/or evaluated by supportive functional studies. In this chapter, we discuss examples of these Other AD Genes. The characterization of the complete list of such genes is beyond the scope of this chapter. As such, the main focus is on alternative strategies for genetic risk factor discovery with highlights of several genes per each approach discussed. Examples of genes identified via the earlier AD GWAS, quantitative endophenotype approaches, functional studies as well as next-generation sequencing (NGS) methodologies are evaluated in this chapter. Identification of the functional variants, additional replication, and further biological investigations are required for widespread acceptance of these as AD risk genes. Nonetheless, this chapter emphasizes the potential utility of alternative approaches besides large disease GWAS in genetic risk discovery for complex diseases like AD. Ultimately multiple complementary research paradigms will be required to uncover the complete genetic risk structure of AD.