Genomic variants, genes, and pathways of Alzheimer's disease: An overview.

Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia. With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets. Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately ∼20 genes with common variants contributing to LOAD risk. In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses. Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple low-frequency and rare variant contributors to AD, and discuss on-going efforts with next-generation sequencing studies to develop statistically well- powered and comprehensive genomic studies of AD. Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD.